N-ureidoalkyl-piperidines as modulators of chemokine receptor activity

ABSTRACT

The present application describes modulators of CCR3 of formula (I):                    
     or pharmaceutically acceptable salt forms thereof, useful for the prevention of asthma and other allergic diseases.

This application is a divisional of application Ser. No. 09/465,287,filed Dec. 17, 1999 now U.S. Pat. No. 6,492,400, which claims thebenefit of provisional application 60/112,717 filed Dec. 18, 1998, andprovisional application 60/161,184 filed Oct. 22, 1999, the contents ofeach of the above are hereby incorporated by reference.

FIELD OF THE INVENTION

This invention relates generally to modulators of chemokine receptoractivity, pharmaceutical compositions containing the same, and methodsof using the same as agents for treatment and prevention of inflammatorydiseases such as asthma and allergic diseases, as well as autoimmunepathologies such as rheumatoid arthritis and atherosclerosis.

BACKGROUND OF THE INVENTION

Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, thatare released by a wide variety of cells to attract and activate, amongother cell types, macrophages, T and B lymphocytes, eosinophils,basophils and neutrophils (reviewed in Luster, New Eng. J Med., 338,436-445 (1998) and Rollins, Blood, 90, 909-928 (1997)). There are twomajor classes of chemokines, CXC and CC, depending on whether the firsttwo cysteines in the amino acid sequence are separated by a single aminoacid (CXC) or are adjacent (CC). The CXC chemokines, such asinterleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) andmelanoma growth stimulatory activity protein (MGSA) are chemotacticprimarily for neutrophils and T lymphocytes, whereas the CC chemokines,such as RANTES, MIP-1α, MIP-1β, the monocyte chemotactic proteins(MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (−1, −2, and−3) are chemotactic for, among other cell types, macrophages, Tlymphocytes, eosinophils, dendritic cells, and basophils. There alsoexist the chemokines lymphotactin-1, lymphotactin-2 (both C chemokines),and fractalkine (a CXXXC chemokine) that do not fall into either of themajor chemokine subfamilies.

The chemokines bind to specific cell-surface receptors belonging to thefamily of G-protein-coupled seven-transmembrane-domain proteins(reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) which aretermed “chemokine receptors.” On binding their cognate ligands,chemokine receptors transduce an intracellular signal through theassociated trimeric G proteins, resulting in, among other responses, arapid increase in intracellular calcium concentration, changes in cellshape, increased expression of cellular adhesion molecules,degranulation, and promotion of cell migration. There are at least tenhuman chemokine receptors that bind or respond to CC chemokines with thefollowing characteristic patterns: CCR-1 (or “CKR-1” or “CC-CKR-1”)[MIP-1α, MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell, 72, 415-425(1993), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-2A andCCR-2B (or “CKR-2A”/“CKR-2B” or “CC-CKR-2A”/“CC-CKR-2B”) [MCP-1, MCP-2,MCP-3, MCP-4, MCP-5] (Charo et al., Proc. Natl. Acad. Sci. USA, 91,2752-2756 (1994), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-3(or “CKR-3” or “CC-CKR-3”) [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4](Combadiere, et al., J. Biol. Chem., 270, 16491-16494 (1995), Luster,New Eng. J. Med., 338, 436-445 (1998)); CCR-4 (or “CKR-4” or “CC-CKR-4”)[TARC, MIP-1α, RANTES, MCP-1] (Power et al., J. Biol. Chem., 270,19495-19500 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998));CCR-5 (or “CKR-5” OR “CC-CKR-5”) [MIP-1α, RANTES, MIP-1β] (Sanson, etal., Biochemistry, 35, 3362-3367 (1996)); CCR-6 (or “CKR-6” or“CC-CKR-6”) [LARC] (Baba et al., J. Biol. Chem., 272, 14893-14898(1997)); CCR-7 (or “CKR-7” or “CC-CKR-7”) [ELC] (Yoshie et al., J.Leukoc. Biol. 62, 634-644 (1997)); CCR-8 (or “CKR-8” or “CC-CKR-8”)[I-309, TARC, MIP-1β] (Napolitano et al., J. Immunol., 157, 2759-2763(1996), Bernardini et al., Eur. J. Immunol., 28, 582-588 (1998)); andCCR-10 (or “CKR-10” or “CC-CKR-10”) [MCP-1, MCP-3] (Bonini et al, DNAand Cell Biol., 16, 1249-1256 (1997)).

In addition to the mammalian chemokine receptors, mammaliancytomegaloviruses, herpesviruses and poxviruses have been shown toexpress, in infected cells, proteins with the binding properties ofchemokine receptors (reviewed by Wells and Schwartz, Curr. Opin.Biotech., 8, 741-748 (1997)). Human CC chemokines, such as RANTES andMCP-3, can cause rapid mobilization of calcium via these virally encodedreceptors. Receptor expression may be permissive for infection byallowing for the subversion of normal immune system surveillance andresponse to infection. Additionally, human chemokine receptors, such asCXCR4, CCR2, CCR3, CCR5 and CCR8, can act as co-receptors for theinfection of mammalian cells by microbes as with, for example, the humanimmunodeficiency viruses (HIV).

Chemokine receptors have been implicated as being important mediators ofinflammatory, infectious, and immunoregulatory disorders and diseases,including asthma and allergic diseases, as well as autoimmunepathologies such as rheumatoid arthritis and atherosclerosis. Forexample, the chemokine receptor CCR-3 plays a pivotal role in attractingeosinophils to sites of allergic inflammation and in subsequentlyactivating these cells. The chemokine ligands for CCR-3 induce a rapidincrease in intracellular calcium concentration, increased expression ofcellular adhesion molecules, cellular degranulation, and the promotionof eosinophil migration. Accordingly, agents which modulate chemokinereceptors would be useful in such disorders and diseases. In addition,agents which modulate chemokine receptors would also be useful ininfectious diseases such as by blocking infection of CCR3 expressingcells by HIV or in preventing the manipulation of immune cellularresponses by viruses such as cytomegaloviruses.

A substantial body of art has accumulated over the past several decadeswith respect to substituted piperidines and pyrrolidines. Thesecompounds have implicated in the treatment of a variety of disorders.

WO 98/25604 describes spiro-substituted azacycles which are useful asmodulators of chemokine receptors:

wherein R₁ is C₁₋₆ alkyl, optionally substituted with functional groupssuch as —NR⁶CONHR⁷, wherein R⁶ and R⁷ may be phenyl further substitutedwith hydroxy, alkyl, cyano, halo and haloalkyl. Such spiro compounds arenot considered part of the present invention.

WO 95/13069 is directed to certain piperidine, pyrrolidine, andhexahydro-1H-azepine compounds of general formula:

wherein A may be substituted alkyl or Z-substituted alkyl, withZ═NR_(6a) or O. Compounds of this type are claimed to promote therelease of growth hormone in humans and animals.

WO 93/06108 discloses pyrrolobenzoxazine derivatives as5-hydroxytryptamine (5-HT) agonists and antagonists:

wherein A is lower alkylene and R⁴ may be phenyl optionally substitutedwith halogen.

U.S. Pat. No. 5,668,151 discloses Neuropeptide Y (NPY) antagonistscomprising 1,4-dihydropyridines with a piperidinyl ortetrahydropyridinyl-containing moiety attached to the 3-position of the4-phenyl ring:

wherein B may be NH, NR¹, O, or a bond, and R⁷ may be substitutedphenyl, benzyl, phenethyl and the like.

These reference compounds are readily distinguished structurally byeither the nature of the urea functionality, the attachment chain, orthe possible substitution of the present invention. The prior art doesnot disclose nor suggest the unique combination of structural fragmentswhich embody these novel piperidines and pyrrolidines as having activitytoward the chemokine receptors.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novelagonists or antagonists of CCR-3, or pharmaceutically acceptable saltsor prodrugs thereof.

It is another object of the present invention to provide pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

It is another object of the present invention to provide a method fortreating inflammatory diseases and allergic disorders comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of the present invention to provide novelN-ureidoalkyl-piperidines for use in therapy.

It is another object of the present invention to provide the use ofnovel N-ureidoalkyl-piperidines for the manufacture of a medicament forthe treatment of allergic disorders.

In another embodiment, the present invention provides novelN-ureidoalkyl-piperidines for use in therapy.

In another embodiment, the present invention provides the use of novelN-ureidoalkyl-piperidines for the manufacture of a medicament for thetreatment of allergic disorders.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat compounds of formula (I):

or stereoisomers or pharmaceutically acceptable salts thereof, whereinE, Z, M, J, K, L, Q, R¹, R², R³, and R⁴ are defined below, are effectivemodulators of chemokine activity.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[1] In one embodiment, the present invention provides novel compounds offormula (I):

or stereoisomers or pharmaceutically acceptable salts thereof, wherein:

M is absent or selected from CH₂, CHR⁵, CHR¹³, CR¹³R¹³, and CR⁵R¹³;

Q is selected from CH₂, CHR⁵, CHR¹³, CR¹³R¹³, and CR⁵R¹³;

J, K, and L are independently selected from CH₂, CHR⁵, CHR⁶, CR⁶R⁶ andCR⁵R⁶;

with the provisos:

1) at least one of M, J, K, L, or Q contains an R⁵; and

2) when M is absent, J is selected from CH₂, CHR⁵, CHR¹³, and CR⁵R¹³;

Z is selected from O and S;

E is selected from:

ring A is phenyl or naphthyl;

R¹ and R² are independently selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(a);

R^(a), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(b)R^(b), (CH₂)_(r)OH, (CH₂)_(r)OR^(c), (CH₂)_(r)SH,(CH₂)_(r)SR^(c), (CH₂)_(r)C(O)R^(b), (CH₂)_(r)C(O)NR^(b)R^(b),(CH₂)_(r)NR^(b)C(O)R^(b), (CH₂)_(r)C(O)OR^(b), (CH₂)_(r)OC(O)R^(c),(CH₂)_(r)CH(═NR^(b))NR^(b)R^(b), (CH₂)_(r)NHC(═NR^(b))NR^(b)R^(b),(CH₂)_(r)S(O)_(p)R^(c), (CH₂)_(r)S(O)₂NR^(b)R^(b),(CH₂)_(r)NR^(b)S(O)₂R^(c), and (CH₂)_(r)phenyl;

R^(b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl;

R^(c), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl,and phenyl;

alternatively, R² and R³ join to form a 5, 6, or 7-membered ringsubstituted with 0-3 R^(a);

R³ is selected from a (CR³′R³″)_(r)—C₃₋₈ carbocyclic residue substitutedwith 1 R¹⁵′ and 0-4 R¹⁵; a (CR³′R³″)_(r)—C₉₋₁₀ carbocyclic residuesubstituted with 0-4 R¹⁵; and a (CR³′R³″)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R¹⁵;

R³′ and R³″, at each occurrence, are selected from H, C₁₋₆ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl;

R⁴ is absent, taken with the nitrogen to which it is attached to form anN-oxide, or selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(q)C(O)R^(4b),(CH₂)_(q)C(O)NR^(4a)R^(4a)′, (CH₂)_(q)C(O)OR^(4b), and a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(4c);

R^(4a) and R^(4a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl;

R^(4b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,(CH₂)_(r)C₃₋₆ cycloalkyl, C₂₋₈ alkynyl, and phenyl;

R^(4c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(4a)R^(4a)′, and (CH₂)_(r)phenyl;

alternatively, R⁴ joins with R⁷, R⁹, R¹¹, or R¹⁴ to form a 5, 6 or 7membered piperidinium spirocycle or pyrrolidinium spirocycle substitutedwith 0-3 R^(a);

R⁵ is selected from a (CR⁵′R⁵″)_(t)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R¹⁶ and a (CR⁵′R⁵″)_(t)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R¹⁶;

R⁵′ and R⁵″, at each occurrence, are selected from H, C₁₋₆ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl;

R⁶, at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CF₂)_(r)CF₃, CN,(CH₂)_(r)NR^(6a)R^(6a)′, (CH₂)_(r)OH, (CH₂)_(r)OR^(6b), (CH₂)_(r)SH,(CH₂)_(r)SR^(6b), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(6b),(CH₂)_(r)C(O)NR^(6a)R^(6a)′, (CH₂)_(r)NR^(6d)C(O)R^(6a),(CH₂)_(r)C(O)OR^(6b), (CH₂)_(r)OC(O)R^(6b), (CH₂)_(r)S(O)_(p)R^(6b),(CH₂)_(r)S(O)₂NR^(6a)R^(6a)′, (CH₂)_(r)NR^(6d)S(O)₂R^(6b), and(CH₂)_(t)phenyl substituted with 0-3 R^(6c);

R^(6a) and R^(6a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(6c);

R^(6b), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl substituted with 0-3 R^(6c);

R^(6c), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,(CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl, and (CH₂)_(r)NR^(6d)R^(6d);

R^(6d), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl;

with the proviso that when any of J, K, or L is CR⁶R⁶ and R⁶ is halogen,cyano, nitro, or bonded to the carbon to which it is attached through aheteroatom, the other R⁶ is not halogen, cyano, or bonded to the carbonto which it is attached through a heteroatom;

R⁷, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(q)OH, (CH₂)_(q)SH, (CH₂)_(q)OR^(7d), (CH₂)_(q)SR^(7d),(CH₂)_(q)NR^(7a)R^(7a)′, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(7b),(CH₂)_(r)C(O)NR^(7a)R^(7a)′, (CH₂)_(q)NR^(7a)C(O)R^(7a),(CH₂)_(q)NR^(7a)C(O)H, (CH₂)_(r)C(O)OR^(7b), (CH₂)_(q)OC(O)R^(7b),(CH₂)_(q)S(O)_(p)R^(7b), (CH₂)_(q)S(O)₂NR^(7a)R^(7a)′,(CH₂)_(q)NR^(7a)S(O)₂R^(7b), C₁₋₆ haloalkyl, a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(7c), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(7c);

R^(7a) and R^(7a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(7e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(7e);

R^(7b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2R^(7e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(7e);

R^(7c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(7f)R^(7f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(7b),(CH₂)_(r)C(O)NR^(7f)R^(7f), (CH₂)_(r)NR^(7f)C(O)R^(7a),(CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(7b),(CH₂)_(r)C(═NR^(7f))NR^(7f)R^(7f), (CH₂)_(r)S(O)_(p)R^(7b),(CH₂)_(r)NHC(═NR^(7f))NR^(7f)R^(7f), (CH₂)_(r)S(O)₂NR^(7f)R^(7f),(CH₂)_(r)NR^(7f)S(O)₂R^(7b), and (CH₂)_(r)phenyl substituted with 0-3R^(7e);

R^(7d), at each occurrence, is selected from C₁₋₆ alkyl substituted with0-3 R^(7e), alkenyl, alkynyl, and a C₃₋₁₀ carbocyclic residuesubstituted with 0-3 R^(7c);

R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;

R^(7f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl;

R⁸ is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(t)phenylsubstituted with 0-3 R^(8a);

R^(8a), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;

alternatively, R⁷ and R⁸ join to form C₃₋₇ cycloalkyl, or ═NR^(8b);

R^(8b) is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, OH, CN, and(CH₂)_(r)-phenyl;

R⁹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, F, Cl,Br, I, NO₂, CN, (CH₂)_(r)OH, (CH₂)_(r)SH, (CH₂)_(r)OR^(9d),(CH₂)_(r)SR^(9d), (CH₂)_(r)NR^(9a)R^(9a)′, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(9b), (CH₂)_(r)C(O)NR^(9a)R^(9a)′,(CH₂)_(r)NR^(9a)C(O)R^(9a), (CH₂)_(r)NR^(9a)C(O)H,(CH₂)_(r)NR^(9a)C(O)NHR^(9a), (CH₂)_(r)C(O)OR^(9b),(CH₂)_(r)OC(O)R^(9b), (CH₂)_(r)OC(O)NHR^(9a), (CH₂)_(r)S(O)_(p)R^(9b),(CH₂)_(r)S(O)₂NR^(9a)R^(9a)′, (CH₂)_(r)NR^(9a)S(O)₂R^(9b), C₁₋₆haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(9c), and a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(9c);

R^(9a) and R^(9a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(9e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(9e);

R^(9b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2R^(9e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(9e);

R^(9c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(9f)R^(9f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(9b),(CH₂)_(r)C(O)NR^(9f)R^(9f), (CH₂)_(r)NR^(9f)C(O)R^(9a),(CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(9b),(CH₂)_(r)C(═NR^(9f))NR^(9f)R^(9f), (CH₂)_(r)S(O)_(p)R^(9b),(CH₂)_(r)NHC(═NR^(9f))NR^(9f)R^(9f), (CH₂)_(r)S(O)₂NR^(9f)R^(9f),(CH₂)_(r)NR^(9f)S(O)₂R^(9b), and (CH₂)_(r)phenyl substituted with 0-3R^(9e);

R^(9d), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(9c),and a 5-6 membered heterocyclic system containing 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R^(9c);

R^(9e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(9f)R^(9f), and (CH₂)_(r)phenyl;

R^(9f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl;

R¹⁰, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, F, Cl,Br, I, NO₂, CN, (CH₂)_(r)OH, (CH₂)_(r)OR^(10d), (CH₂)_(r)SR^(10d),(CH₂)_(r)NR^(10a)R^(10a)′, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(10b),(CH₂)_(r)C(O)NR^(10a)R^(10a)′, (CH₂)_(r)NR^(10a)C(O)R^(10a),(CH₂)_(r)NR^(10a)C(O)H, (CH₂)_(r)C(O)OR^(10b), (CH₂)_(r)OC(O)R^(10b),(CH₂)_(r)S(O)_(p)R^(10b), (CH₂)_(r)S(O)₂NR^(10a)R^(10a)′,(CH₂)_(r)NR^(10a)S(O)₂R^(10b), C₁₋₆ haloalkyl, a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(10c), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(10c);

R^(10a) and R^(10a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(10e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(10e);

R^(10b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2R^(10e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(10e);

R^(10c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(10f)R^(10f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(10b),(CH₂)_(r)C(O)NR^(10f)R^(10f), (CH₂)_(r)NR^(10f)C(O)R^(10a),(CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(10b),(CH₂)_(r)C(═NR^(10f))NR^(10f)R^(10f), (CH₂)_(r)S(O)_(p)R^(10b),(CH₂)_(r)NHC(═NR^(10f))NR^(10f)R^(10f), (CH₂)_(r)S(O)₂NR^(10f)R^(10f),(CH₂)_(r)NR^(10f)S(O)₂R^(10b), and (CH₂)_(r)phenyl substituted with 0-3R^(10e);

R^(10d), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(10c),and a 5-6 membered heterocyclic system containing 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R^(10c);

R^(10e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(10f)R^(10f), and (CH₂)_(r)phenyl;

R^(10f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆cycloalkyl;

alternatively, R⁹ and R¹⁰ join to form C₃₋₇ cycloalkyl, 5-6-memberedcyclic ketal or ═O;

with the proviso that when R¹⁰ is halogen, cyano, nitro, or bonded tothe carbon to which it is attached through a heteroatom, R⁹ is nothalogen, cyano, or bonded to the carbon to which it is attached througha heteroatom;

R¹¹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(q)OH, (CH₂)_(q)SH, (CH₂)_(q)OR^(11d), (CH₂)_(q)SR^(11d),(CH₂)_(q)NR^(11a)R^(11a)′, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(11b),(CH₂)_(r)C(O)NR^(11a)R^(11a)′, (CH₂)_(q)NR^(11a)C(O)R^(11a),(CH₂)_(q)NR^(11a)C(O)NHR^(11a), (CH₂)_(r)C(O)OR^(11b),(CH₂)_(q)OC(O)R^(11b), (CH₂)_(q)S(O)_(p)R^(11b),(CH₂)_(q)S(O)₂NR^(11a)R^(11a)′, (CH₂)_(q)NR^(11a)S(O)₂R^(11b), C₁₋₆haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(11c), and a (CH₂)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(11c);

R^(11a) and R^(11a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(11e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(11e);

R^(11b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2R^(11e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e);

R^(11c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(11f)R^(11f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(11b),(CH₂)_(r)C(O)NR^(11f)R^(11f), (CH₂)_(r)NR^(11f)C(O)R^(11a),(CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(11b),(CH₂)_(r)C(═NR^(11f))NR^(11f)R^(11f),(CH₂)_(r)NHC(═NR^(11f))NR^(11f)R^(11f), (CH₂)_(r)S(O)_(p)R^(11b),(CH₂)_(r)S(O)₂NR^(11f)R^(11f), (CH₂)_(r)NR^(11f)S(O)₂R^(11b), and(CH₂)_(r)phenyl substituted with 0-3 R^(11e);

R^(11d), at each occurrence, is selected from C₁₋₆ alkyl substitutedwith 0-3 R^(11e), C₂₋₆ alkenyl, C₂₋₆ alkynyl, and a C₃₋₁₀ carbocyclicresidue substituted with 0-3 R^(11c);

R^(11e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl; R^(11f), at eachoccurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl;

R¹² is selected from H, C₁₋₆ alkyl, (CH₂)_(q)OH, (CH₂)_(r)C₃₋₆cycloalkyl, and (CH₂)_(t)phenyl substituted with 0-3 R^(12a);

R^(12a), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(9f)R^(9f), and (CH₂)_(r)phenyl;

alternatively, R¹¹ and R¹² join to form C₃₋₇ cycloalkyl;

R¹³, at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C₃₋₆ cycloalkyl, (CF₂)_(w)CF₃, (CH₂)_(r)NR^(13a)R^(13a)′,(CH₂)_(r)OH, (CH₂)_(r)OR^(13b), (CH₂)_(r)SH, (CH₂)_(r)SR^(13b),(CH₂)_(w)C(O)OH, (CH₂)_(w)C(O)R^(13b), (CH₂)_(w)C(O)NR^(13a)R^(13a)′,(CH₂)_(r)NR^(13d)C(O)R^(13a), (CH₂)_(w)C(O)OR^(13b),(CH₂)_(r)OC(O)R^(13b), (CH₂)_(w)S(O)_(p)R^(13b),(CH₂)_(w)S(O)₂NR^(13a)R^(13a)′, (CH₂)_(r)NR^(13d)S(O)₂R^(13b), and(CH₂)_(w)-phenyl substituted with 0-3 R^(13c);

R^(13a) and R^(13a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(13c);

R^(13b), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl substituted with 0-3 R^(13c);

R^(13c), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,(CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl, and (CH₂)_(r)NR^(13d)R^(13d);

R^(13d), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl;

R¹⁴, at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(14a)R^(14a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(14d),(CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(14d),(CHR′)_(r)C(O) OH, (CHR′)_(r)C(O) (CHR′)_(r)R^(14b),(CHR′)_(r)C(O)NR^(14a)R^(14a)′, (CHR′)_(r)NR^(14f)C(O)(CHR′)_(r)R^(14b), (CHR′)_(r)C(O)O(CHR′)_(r)R^(14d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(14b), (CHR′)_(r)C(═NR^(14f))NR^(14a)R^(14a)′,(CHR′)_(r)NHC(═NR^(14f))NR^(14f)R^(14f),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(14b), (CHR′)_(r)S(O)₂NR^(14a)R^(14a)′,(CHR′)_(r)NR^(14f)S(O)₂(CHR′)_(r)R^(14b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(14e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e), or two R¹⁴ substituents onadjacent atoms on ring A form to join a 5-6 membered heterocyclic systemcontaining 1-3 heteroatoms selected from N, O, and S substituted with0-2 R^(15e);

alternatively, R¹⁴ joins with R⁴ to form a 5, 6 or 7 memberedpiperidinium spirocycle or pyrrolidinium spirocycle fused to ring A, thespirocycle substituted with 0-3 R^(a);

R′, at each occurrence, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substitutedwith R^(14e);

R^(14a) and R^(14a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(14e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(14e);

R^(14b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3R^(14e), and (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(14e);

R^(14d), at each occurrence, is selected from C₂₋₈ alkenyl, C₂₋₈alkynyl, C₁₋₆ alkyl substituted with 0-3 R^(14e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(14e), and a (CH₂)_(r)5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(14e);

R^(14e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃-₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(14f)R^(14f), and (CH₂)_(r)phenyl;

R^(14f), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl;

R¹⁵, at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(15a)R^(15a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(15d),(CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(15d),(CHR′)_(r)C(O)OH, (CHR′)_(r)C(O) (CHR′)_(r)R^(15b),(CHR′)_(r)C(O)NR^(15a)R^(15a)′, (CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b), (CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b), ((CHR′)_(r)C(═NR^(15f))NR^(15a)R^(15a)′,(CHR′)_(r)NHC(═NR^(15f))NR^(15f)R^(15f),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)₂NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e);

R¹⁵′, at each occurrence, is selected from C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, (CHR′)_(r)NR^(15a)R^(15a)′,(CHR′)_(r)O(CHR′)_(r)R^(15d), (CHR′)_(r)SH, (CHR′)₃₋₅C(O)H,(CHR′)_(r)S(CHR′)_(r)R^(15d), (CHR′)_(q)C(O) OH, (CHR′)_(q)C(O)(CHR′)_(q)R^(15b), (CHR′)_(r)C(O)NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)C(O) (CHR′)_(r)R^(15b),(CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O) (CHR′)_(r)R^(15b),(CHR′)_(r)C(═NR^(15f))NR^(15a)R^(15a)′,(CHR′)_(r)NHC(═NR^(15f))NR^(15f)R^(15f),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)₂NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₂₋₈ alkenyl substituted with0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, (CHR′)_(r)phenylsubstituted with 0-3 R^(15e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(15e);

R^(15a) and R^(15a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(15e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(15e);

R^(15b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3R^(15e), and (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);

R^(15d), at each occurrence, is selected from C₂₋₈ alkenyl, C₂₋₈alkynyl, C₁₋₆ alkyl substituted with 0-3 R^(15e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(15e), and a (CH₂)_(r)5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(15e);

R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(15f)R^(15f), and (CH₂)_(r)phenyl;

R^(15f), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl;

R¹⁶, at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(16a)R^(16a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(16d),(CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(16d),(CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)C(O)NR^(16a)R^(16a)′, (CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)C(O)O(CHR′)_(r)R^(16d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(16b),(CHR′)_(r)C(═NR^(16f))NR^(16a)R^(16a)′,(CHR′)_(r)NHC(═NR^(16f))NR^(16f)R^(16f),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂NR^(16a)R^(16a)′,(CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and(CHR′)_(r)phenyl substituted with 0-3 R^(16e);

R^(16a) and R^(16a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(16e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(16e);

R^(16b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3R^(16e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(16e);

R^(16d), at each occurrence, is selected from C₂₋₈ alkenyl, C₂₋₈alkynyl, C₁₋₆ alkyl substituted with 0-3 R^(16e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(16e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(16e);

R^(16e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(16f)R^(16f), and (CH₂)_(r)phenyl;

R^(16f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl, and phenyl;

g is selected from 0, 1, 2, 3, and 4;

t is selected from 1 and 2;

w is selected from 0 and 1;

r is selected from 0, 1, 2, 3, 4, and 5;

q is selected from 1, 2, 3, 4, and 5; and

p is selected from 0, 1, 2, and 3.

[2] In a preferred embodiment, the present invention provides novelcompounds of formula (I), wherein:

Z is selected from O and S;

E is selected from:

R⁴ is absent, taken with the nitrogen to which it is attached to form anN-oxide, or selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and(CH₂)_(r)-phenyl substituted with 0-3 R^(4c);

R^(4c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(4a)R^(4a)′, and (CH₂)_(r)phenyl;

alternatively, R⁴ joins with R⁷ R⁹, or R¹⁴ to form a 5, 6 or 7 memberedpiperidinium spirocycle substituted with 0-3 R^(a);

R¹ and R² are independently selected from H and C₁₋₄ alkyl;

R⁶, at each occurrence, is selected from C₁₋₄ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CF₂)_(r)CF₃, CN, (CH₂)_(r)OH,(CH₂)_(r)OR^(6b), (CH₂)_(r)C(O)R^(6b), (CH₂)_(r)C(O)NR^(6a)R^(6a)′,(CH₂)_(r)NR^(6d)C(O)R^(6a), and (CH₂)_(t)phenyl substituted with 0-3R^(6c);

R^(6a) and R^(6a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(6c);

R^(6b), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl substituted with 0-3 R^(6c);

R^(6c), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,(CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl, and (CH₂)_(r)NR^(6d)R^(6d);

R^(6d), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl;

R⁷, is selected from H, C₁₋₃ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl,(CH₂)_(q)OH, (CH₂)_(q)OR^(7d), (CH₂)_(q)NR^(7a)R^(7a)′,(CH₂)_(r)C(O)R^(7b), (CH₂)_(r)C(O)NR^(7a)R^(7a)′,(CH₂)_(q)NR^(7a)C(O)R^(7a), C₁₋₆ haloalkyl, (CH₂)_(r)phenyl with 0-2R^(7c);

R^(7a) and R^(7a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)phenyl substituted with 0-3 R^(7e);

R^(7b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(r)phenyl substituted with0-3 R^(7e);

R^(7c), at each occurrence, is selected from C₁₋₄ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(7f)R^(7f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)C(O)R^(7b), (CH₂)_(r)C(O)NR^(7f)R^(7f),(CH₂)_(r)NR^(7f)C(O)R^(7a), (CH₂)_(r)S(O)_(p)R^(7b),(CH₂)_(r)S(O)₂NR^(7f)R^(7f), (CH₂)_(r)NR^(7f)S(O)₂R^(7b), and(CH₂)_(r)phenyl substituted with 0-2 R^(7e);

R^(7d), at each occurrence, is selected from C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, (CH₂)_(r)phenyl substituted with 0-3 R^(7e);

R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;

R^(7f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆cycloalkyl;

R⁸ is H or joins with R⁷ to form C₃₋₇ cycloalkyl or ═NR^(8b);

R¹¹, is selected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl,(CH₂)_(q)OH, (CH₂)_(q)OR^(11d), (CH₂)_(q)NR^(11a)R^(11a)′,(CH₂)_(r)C(O)R^(11b), (CH₂)_(r)C(O)NR^(11a)R^(11a)′,(CH₂)_(q)NR^(11a)C(O)R^(11a), C₁₋₆ haloalkyl, (CH₂)_(r)phenyl with 0-2R^(11c), (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R¹⁵;

R^(11a) and R^(11a)′, at each occurrence, are selected from H, C₁₋₆alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)phenyl substituted with 0-3R^(11e);

R^(11b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(r)phenyl substituted with0-3 R^(11e);

R^(11c), at each occurrence, is selected from C₁₋₄ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(11f)R^(11f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)C(O)R^(11b), (CH₂)_(r)C(O)NR^(11f)R^(11f),(CH₂)_(r)NR^(11f)C(O)R^(11a), (CH₂)_(r)S(O)_(p)R^(11b),(CH₂)_(r)S(O)₂NR^(11f)R^(11f), (CH₂)_(r)NR^(11f)S(O)₂R^(11b), and(CH₂)_(r)phenyl substituted with 0-2 R^(11e);

R^(11d), at each occurrence, is selected from C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, (CH₂)_(r)phenyl substituted with 0-3 R^(11e);

R^(11e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl;

R^(11f), at each occurrence, is selected from H, C₁₋₅ alkyl and C₃₋₆cycloalkyl;

R¹² is H or joins with R¹¹ to form C₃₋₇ cycloalkyl;

R¹³, at each occurrence, is selected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl,(CH₂)NR^(13a)R^(13a)′, (CH₂)OH, (CH₂)OR^(13b), (CH₂)_(w)C(O)R^(13b),(CH₂)_(w)C(O)NR^(13a)R^(13a)′, (CH₂)NR^(13d)C(O)R^(13a),(CH₂)_(w)S(O)₂NR^(13a)R^(13a)′, (CH₂)NR^(13d)S(O)₂R^(13b), and(CH₂)_(w)-phenyl substituted with 0-3 R^(13c);

R^(13a) and R^(13a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(13c);

R^(13b), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl substituted with 0-3 R^(13c);

R^(13c), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,(CH₂)_(r)OH, and (CH₂)_(r)NR^(13d)R^(13d);

R^(13d), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl;

q is selected from 1, 2, and 3; and

r is selected from 0, 1, 2, and 3.

[3] In a more preferred embodiment, the present invention provides novelcompounds of formula (I), wherein:

ring A is selected from:

R³ is selected from a (CR³′H)_(r)—C₃₋₈ carbocyclic residue substitutedwith 1 R¹⁵′ and 0-4 R¹⁵, wherein the C₃₋₈ carbocyclic residue isselected from phenyl, C₃₋₆ cycloalkyl; a (CR³′H)_(r)—C₉₋₁₀ carbocyclicresidue substituted with 0-4 R¹⁵, wherein the C₉₋₁₀ carbocyclic residueis selected from naphthyl and adamantyl; and a (CR³′H)_(r)-heterocyclicsystem substituted with 0-3 R¹⁵, wherein the heterocyclic system isselected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl,benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl,benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl,indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl,pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl,thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and

R⁵ is selected from (CR⁵′H)_(t)-phenyl substituted with 0-5 R¹⁶; and a(CR⁵′H)_(t)-heterocyclic system substituted with 0-3 R¹⁶, wherein theheterocyclic system is selected from pyridinyl, thiophenyl, furanyl,indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl,imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl,1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl.

[4]In an even more preferred embodiment, the present invention providesnovel compounds of formula (I-i), wherein the compound of formula (I-i)is:

with the proviso that at least one of J, K, or L contains an R⁵;

R¹⁶, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(16a)R^(16a)′, NO₂, CN, OH,(CH₂)_(r)OR^(16d), (CH₂)_(r)C(O)R^(16b), (CH₂)_(r)C(O)NR^(16a)R^(16a)′,(CH₂)_(r)NR^(16f)C(O)R^(16b), (CH₂)_(r)S(O)_(p)R^(16b),(CH₂)_(r)S(O)₂NR^(16a)R^(16a)′, (CH₂)_(r)NR^(16f)S(O)₂R^(16b), and(CH₂)_(r)phenyl substituted with 0-3 R^(16e);

R^(16a) and R^(16a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3R^(16e);

R^(16b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(16e);

R^(16d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(16e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and

R^(16f), at each occurrence, is selected from H, and C₁₋₅ alkyl.

[5] In an another even more preferred embodiment, the present inventionprovides novel compounds of formula (I-ii), wherein (I-ii) is:

with the proviso that at least one of K or L contains an R⁵;

R¹⁶, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(16a)R^(16a)′, NO₂, CN, OH,(CH₂)_(r)OR^(16d), (CH₂)_(r)C(O)R^(16b), (CH₂)_(r)C(O)NR^(16a)R^(16a)′,(CH₂)_(r)NR^(16f)C(O)R^(16b), (CH₂)_(r)S(O)_(p)R^(16b),(CH₂)_(r)S(O)₂NR^(16a)R^(16a)′, (CH₂)_(r)NR^(16f)S(O)₂R^(16b), and(CH₂)_(r)phenyl substituted with 0-3 R^(16e);

R^(16a) and R^(16a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3R^(16e);

R^(16b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(16e);

R^(16d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(16e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and

R^(16f), at each occurrence, is selected from H, and C₁₋₅ alkyl.

[6] In a preferred embodiment, the present invention provides novelcompounds of formula (I-i), wherein:

R⁵ is CH₂phenyl substituted with 0-3 R¹⁶;

R⁹, is selected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, F, Cl, CN,(CH₂)_(r)OH, (CH₂)_(r)OR^(9d), (CH₂)_(r)NR^(9a)R^(9a)′,(CH₂)_(r)OC(O)NHR^(9a), (CH₂)_(r)phenyl substituted with 0-5 R^(9e), anda heterocyclic system substituted with 0-2 R^(9e), wherein theheterocyclic system is selected from pyridyl, thiophenyl, furanyl,oxazolyl, and thiazolyl;

R^(9a) and R^(9a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(9e);

R^(9d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(9e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl;

R¹⁰ is selected from H, C₁₋₅ alkyl, OH, and CH₂OH;

alternatively, R⁹ and R¹⁰ join to form C₃₋₇ cycloalkyl, 5-6-memberedcyclic ketal or ═O;

with the proviso that when R¹⁰ is halogen, cyano, nitro, or bonded tothe carbon to which it is attached through a heteroatom, R⁹ is nothalogen, cyano, or bonded to the carbon to which it is attached througha heteroatom;

R¹¹ is selected from H, C₁₋₈ alkyl, (CH₂)_(r)phenyl substituted with 0-5R^(11e), and a (CH₂)_(r)-heterocyclic system substituted with 0-2R^(11e), wherein the heterocyclic system is selected from pyridinyl,thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl,1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl; and

R^(11e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl;

R¹² is H;

alternatively, R¹¹ and R¹² join to form C₃₋₇ cycloalkyl;

R¹⁴, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(14a)R^(14a)′, NO₂, CN, OH,(CH₂)_(r)OR^(14d), (CH₂)_(r)C(O)R^(14b), (CH₂)_(r)C(O)NR^(14a)R^(14a)′,(CH₂)_(r)NR^(14f)C(O)R^(14b), (CH₂)_(r)S(O)_(p)R^(14b),(CH₂)_(r)S(O)₂NR^(14a)R^(14a)′, (CH₂)_(r)NR^(14f)S(O)₂R^(14b),(CH₂)_(r)phenyl substituted with 0-3 R^(14e);

R^(14a) and R^(14a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3R^(14e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);

R^(14b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(14e);

R^(14d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(14e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and

R^(14f), at each occurrence, is selected from H, and C₁₋₅ alkyl; and

r is selected from 0, 1, and 2.

[7] In a preferred embodiment, the present invention provides novelcompounds of formula (I-ii), wherein:

R⁵ is CH₂phenyl substituted with 0-3 R¹⁶;

R⁹, is selected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, F, Cl, CN,(CH₂)_(r)OH, (CH₂)_(r)OR^(9d), (CH₂)_(r)NR^(9a)R^(9a)′,(CH₂)_(r)OC(O)NHR^(9a), (CH₂)_(r)phenyl substituted with 0-5 R^(9e), anda heterocyclic system substituted with 0-2 R^(9e), wherein theheterocyclic system is selected from pyridyl, thiophenyl, furanyl,oxazolyl, and thiazolyl;

R^(9a) and R^(9a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(9e);

R^(9d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(9e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl;

R¹⁰ is selected from H, C₁₋₈ alkyl, OH, and CH₂OH;

alternatively, R⁹ and R¹⁰ join to form C₃₋₇ cycloalkyl, 5-6-memberedcyclic ketal or ═O;

with the proviso that when R¹⁰ is halogen, cyano, nitro, or bonded tothe carbon to which it is attached through a heteroatom, R⁹ is nothalogen, cyano, or bonded to the carbon to which it is attached througha heteroatom; R¹¹ is selected from H, C₁₋₈ alkyl, (CH₂)_(r)phenylsubstituted with 0-5 R^(11e), and a (CH₂)_(r)-heterocyclic systemsubstituted with 0-2 R^(11e), wherein the heterocyclic system isselected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl,benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl,benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl,isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl,tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and

R^(11e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl;

R¹² is H;

alternatively, R¹¹ and R¹² join to form C₃₋₇ cycloalkyl;

R¹⁴, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(14a)R^(14a)′, NO₂, CN, OH,(CH₂)_(r)OR^(14d), (CH₂)_(r)C(O)R^(14b), (CH₂)_(r)C(O)NR^(14a)R^(14a)′,(CH₂)_(r)NR^(14f)C(O)R^(14b), (CH₂)_(r)S(O)_(p)R^(14b),(CH₂)_(r)S(O)₂NR^(14a)R^(14a)′, (CH₂)_(r)NR^(14f)S(O)₂R^(14b),(CH₂)_(r)phenyl substituted with 0-3 R^(14e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e), or two R¹⁴ substituents onadjacent atoms on ring A form to join a 5-6 membered heterocyclic systemcontaining 1-3 heteroatoms selected from N, O, and S substituted with0-2 R^(15e);

R^(14a) and R^(14a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3R^(14e);

R^(14b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(14e);

R^(14d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(14e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl;

R^(14f), at each occurrence, is selected from H, and C₁₋₅ alkyl; and

r is selected from 0, 1, and 2.

[8] In a more preferred embodiment, the present invention provides novelcompounds of formula (I-i), wherein:

J is selected from CH₂ and CHR⁵;

L is selected from CH₂ and CHR⁵;

R³ is selected from a C₃₋₈ carbocyclic residue substituted with 1 R¹⁵′and 0-3 R¹⁵, wherein the C₃₋₈ carbocyclic residue is selected fromcyclopropyl, cyclopentyl, cyclohexyl, and phenyl; a C₉₋₁₀ carbocyclicresidue substituted with 0-3 R¹⁵, wherein the C₉₋₁₀ carbocyclic residueis selected from naphthyl and adamantyl; and a (CR³′H)_(r)-heterocyclicsystem substituted with 0-3 R¹⁵, wherein the heterocyclic system isselected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl,benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl,benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl,indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl,pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl,thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and

R¹⁵, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(15a)R^(15a)′, NO₂, CN, OH,(CH₂)_(r)OR^(15d), (CH₂)_(r)C(O)R^(15b), (CH₂)_(r)C(O)NR^(15a)R^(15a)′,(CH₂)_(r)NR^(15f)C(O)R^(15b), (CH₂)_(r)S(O)_(p)R^(15b),(CH₂)_(r)S(O)₂NR^(15a)R^(15a)′, (CH₂)_(r)NR^(15f)S(O)₂R^(15b),(CH₂)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e);

R^(15a) and R^(15a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3R^(15e);

R^(15b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(15e);

R^(15d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and

R^(15f), at each occurrence, is selected from H, and C₁₋₅ alkyl.

[9] In a more preferred embodiment, the present invention provides novelcompounds of formula (I-ii), wherein:

L is selected from CH₂ and CHR⁵;

R³ is selected from a C₃₋₈ carbocyclic residue substituted with 1 R¹⁵′and 0-3 R¹⁵, wherein the C₃₋₈ carbocyclic residue is selected fromcyclopropyl, cyclopentyl, cyclohexyl, and phenyl; a C₉₋₁₀ carbocyclicresidue substituted with 0-3 R¹⁵, wherein the C₉₋₁₀ carbocyclic residueis selected from naphthyl and adamantyl; and a (CR³′H)_(r)-heterocyclicsystem substituted with 0-3 R¹⁵, wherein the heterocyclic system isselected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl,benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl,benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl,indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl,pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl,thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and

R¹⁵, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(15a)R^(15a)′, NO₂, CN, OH,(CH₂)_(r)OR^(15d), (CH₂)_(r)C(O)R^(15b), (CH₂)_(r)C(O)NR^(15a)R^(15a)′,(CH₂)_(r)NR^(15f)C(O)R^(15b), (CH₂)_(r)S(O)_(p)R^(15b),(CH₂)_(r)S(O)₂NR^(15a)R^(15a)′, (CH₂)_(r)NR^(15f)S(O)₂R^(15b), and(CH₂)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e);

R^(15a) and R^(15a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3R^(15e);

R^(15b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(15e);

R^(15d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and

R^(15f), at each occurrence, is selected from H and C₁₋₅ alkyl.

[10] In a further even more preferred embodiment, the present inventionprovides novel compounds of formula (I) and pharmaceutically acceptablesalt forms thereof, wherein the compound of formula (I) is selectedfrom:

N-[1-(phenylmethyl)-4-piperidinyl]-N′-[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N-(2,5-difluorophenyl)-N′-[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N-(2,5-difluorophenyl)-N′-[[3-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]methyl]urea,

N-(2,5-difluorophenyl)-N′-[2-[[4-(phenylmethyl)-1-piperidinyl]acetyl]phenyl]urea,

N-(2,5-difluorophenyl)-N′-[2-[[1-hydroxy-2-[4-(phenylmethyl)-piperidinyl]ethyl]phenyl]urea,

N-[3-[imino-[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]-N′-phenylurea,

N-[1-(phenylmethyl)-4-piperidinyl]-N′-[3-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N-[2-(4-fluorophenyl)ethyl]-N′-[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N-[3-hydroxypropyl]-N′-[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N-[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]-N′-[2-(1-piperidinyl)ethyl]urea,

N-[2-(dimethylamino)ethyl]-N′-[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

4-(phenylmethyl)-N-[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]-1-piperazinecarboxamide,

4-(phenylmethyl)-N-[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]-1-piperidinecarboxamide,

N-(1,3-benzodioxol-5-ylmethyl)-N′-[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N-[2,2-(diphenyl)ethyl]-N′-[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

4-(4-chlorophenyl)-4-hydroxy-N-[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]-1-piperidinecarboxamide,

4-phenyl-4-hydroxy-N-[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]-1-piperidinecarboxamide,

4-phenyl-N-[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]-1-piperidinecarboxamide,

N-1H-indazol-5-yl-N′-[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N-1H-indazol-6-yl-N′-[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N-[phenylmethyl]-N′-[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N-1,3-benzodioxol-5-yl-N′-[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N-[1-(phenylmethyl)-4-piperidinyl]-N′-[6-[[4-(phenylmethyl)-1-piperidinyl]methyl]-1,3-benzodioxol-5-yl]urea,

N-[2-(4-fluorophenyl)ethyl]-N′-[6-[[4-(phenylmethyl)-1-piperidinyl]methyl]-1,3-benzodioxol-5-yl]urea,

4-((2-phenyl)ethyl)-N-[6-[[4-(phenylmethyl)-1-piperidinyl]methyl]-1,3-benzodioxol-5-yl]-1-piperazinecarboxamide,

N-1H-indazol-5-yl-N′-[6-[[4-(phenylmethyl)-1-piperidinyl]methyl]-1,3-benzodioxol-5-yl]urea,

N-1H-indazol-6-yl-N′-[6-[[4-(phenylmethyl)-1-piperidinyl]methyl]-1,3-benzodioxol-5-yl]urea,

N-benzothiazol-6-yl-N′-[6-[[4-(phenylmethyl)-1-piperidinyl]methyl]-1,3-benzodioxol-5-yl]urea,

N-[2-(4-fluorophenyl)ethyl]-N′-[4-hydroxy-2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N-[4-hydroxy-2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]-N′-[1-(phenylmethyl)-4-piperidinyl]urea,

N-[3-phenylpropyl]-N′-[6-[[4-(phenylmethyl)-1-piperidinyl]methyl]-1,3-benzodioxol-5-yl]urea,

N-1H-indazol-5-yl-N′-[3-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N-[2-(4-fluorophenyl)ethyl]-N′-[3-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N-(2,5-difluorophenyl)-N′-[2-[4-(phenylmethyl)-1-piperidinyl]phenyl]urea,

N-phenyl-N′-[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N-(4-methoxyphenyl)-N′-[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N-(3-methoxyphenyl)-N′-[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N′-(3-cyanophenyl)-N-[3-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N′-(3-cyanophenyl)-N-[4-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N-[2-phenylethyl]-N′-[4-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

Ethyl-3-[[[[2-[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]amino]carbonyl]amino]benzoate,

N′-(3-cyanophenyl)-N-[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N-phenyl-N′-[2-[[4-(4-fluorophenyl)methyl-1-piperidinyl]methyl]phenyl]urea,

N′-(phenyl)-N-(phenylmethyl)-N-[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N′-(3-cyanophenyl)-N-(phenylmethyl)-N-[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N-[2-phenylethyl]-N′-[2-[[4-(phenylmethyl)-piperidinyl]methyl]phenyl]urea,

N-(3-cyanophenyl)-N′-[6-[[4-(phenylmethyl)-1-piperidinyl]methyl]-1,3-benzodioxol-5-yl]urea,

Ethyl-3-[[[[6-[[4-(phenylmethyl)-1-piperidinyl]methyl]-1,3-benzodioxol-5-yl]amino]carbonyl]amino]benzoate,

Ethyl-4-[[[[6-[[4-(phenylmethyl)-1-piperidinyl]methyl]-1,3-benzodioxol-5-yl]amino]carbonyl]amino]benzoate,

N-[4-hydroxy-2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]-N′-[phenyl]urea,

N-[3-cyanophenyl]-N′-[4-hydroxy-2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N-[4-[(methylsulfonyl)oxy]-2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]-N′-[3-methoxyphenyl]urea,

N-[4-[(methylsulfonyl)oxy]-2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]-N′-(2-phenylcyclopropyl)urea,

Methyl-3-[[[(3-cyanophenyl)amino]carbonyl]amino]-4-[[4-(phenylmethyl)-1-piperidinyl]methyl]benzoate,

Methyl-3-[[[(3-methoxyphenyl)amino]carbonyl]amino]-4-[[4-(phenylmethyl)-1-piperidinyl]methyl]benzoate,

N-[4-[(methylsulfonyl)oxy]-2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]-N′-[3-cyanophenyl]urea,

N-[5-hydroxymethyl-2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]-N′-[3-methoxyphenyl]urea,

N-(3-cyanophenyl)-N′-[5-(hydroxymethyl)-2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

Methyl-4-[[[(3-cyanophenyl)amino]carbonyl]amino]-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]benzoate,

Methyl-3-[[[(3-cyanophenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-benzoate,

3-[[[(3-cyanophenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-N-methylbenzamide

3-[[[(3-cyanophenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]benzamide,

Methyl-3-[[[3-(1-hydroxyethyl)phenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-benzoate,

3-[[[(phenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]benzoic acid,

Methyl-3-[[[(3-acetylphenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-benzoatehydrochloride

Methyl-4-[[[phenylamino]carbonyl]amino]-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]benzoate,

Methyl-3-[[[(phenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-benzoate,

3-[[[(phenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-N-methylbenzamide,

3-[[[(phenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]benzamide,

Methyl-4-[[[(3-methoxyphenyl)amino]carbonyl]amino]-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]benzoate,

Methyl-3-[[[(3-methoxyphenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorohenyl)methyl]-1-piperidinyl]methyl]-benzoate,

3-[[[(3-methoxyphenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-N-methylbenzamide,

Methyl-3-[[[(3-acetylphenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-benzoate,

3-[[[(3-acetylphenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-N-methylbenzamide

3-[[[(3-acetylphenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]benzamide,

N-[4-hydroxymethyl-2-[[4-(4-fluorophenylmethyl)-1-piperidinyl]methyl]phenyl]-N′-[3-cyanophenyl]urea,

N-(3-cyanophenyl)-N′-[2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1-naphthalenyl]urea,

N-[2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1-naphthalenyl]-N′-(3-methoxyphenyl)urea,

4-[[[(3-cyanophenyl)amino]carbonyl]amino]-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-N-phenylbenzamide,

3-[[[(3-cyanophenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-N-phenylbenzamide,

3-[[[(3-acetylphenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-N-phenylbenzamide,

N-[4-hydroxymethyl-2-[[4-(4-fluorophenylmethyl)-1-piperidinyl]methyl]phenyl]-N′-[3-methoxyphenyl]urea,

4-[[[(3-cyanophenyl)amino]carbonyl]amino]-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-N-methylbenzamide,

3-[[[(3-cyanophenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-N-methylbenzamide hydrochloride

3-[[[(3-acetylphenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-N-methylbenzamide hydrochloride

3-[[[(3-acetylphenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-N-[2-(N,N-dimethylamino)ethyl]benzamide

3-[[[(3-cyanophenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-N-[2-(N,N-dimethylamino)ethyl]benzamide

3-[[[(3-acetylphenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-N-[cyclopropyl]benzamide

3-[[[(3-cyanophenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-N-[cyclopropyl]benzamide

3-[[[(3-methoxyphenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-N,N-dimethylbenzamide

3-[[[(3-acetylphenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-N,N-dimethylbenzamide

3-[[[(3-acetylphenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-N(pyridin-2-yl)benzamide

3-[[[(3-methoxyphenyl)amino]carbonyl]amino]-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-N(pyridin-2-yl)benzamide,

N-(2,5-difluorophenyl)-N′-[[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]methyl]urea,

N-(3-cyanophenyl)-N′-[[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]methyl]urea,

Ethyl-3-[[[[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]amino]carbonyl]amino]benzoate,

N-(3-methoxyphenyl)-N′-[[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]methyl]urea,

N-(4-methoxyphenyl)-N′-[[2-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]methyl]urea,

N-(3-methoxyrophenyl)-N′-[2-[[1-hydroxy-2-[4-(phenylmethyl)-1-piperidinyl]ethyl]phenyl]urea,

N-(3-cyanophenyl)-N′-[2-[[1-hydroxy-2-[4-(phenylmethyl)-1-piperidinyl]ethyl]phenyl]urea,

Ethyl-3-[[[[2-[1-hydroxy-2-[4-(phenylmethyl)-1-piperidinyl]ethyl]phenyl]amino]carbonyl]amino]benzoate,

N-(phenyl)-N′-[2-[[1-hydroxy-2-[4-(phenylmethyl)-1-piperidinyl]ethyl]phenyl]urea,

N-(phenyl)-N′-[3-(hydroxymethyl)-2-[[4-(4-fluorophenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N-[2-[1-hydroxyimino)-2-[4-(phenylmethyl)-1-piperidinyl]ethyl]phenyl]-N′-phenylurea,

N-(phenyl)-N′-[3-[[4-(phenylmethyl)-1-piperidinyl]acetyl]phenyl]urea,

N-(phenyl)-N′-[3-[[1-hydroxy-2-[4-phenylmethyl)-1-piperidinyl]ethyl]phenyl]urea,

N-(phenyl)-N′-[2-[[1-hydroxy-2-[4-(4-fluorophenyl)methyl)-1-piperidinyl]ethyl]phenyl]urea,

N-(3-methoxyphenyl)-N′-[2-[[1-hydroxy-2-[4-(4-fluorophenyl)methyl)-1-piperidinyl]ethyl]phenyl]urea,

N-(3-cyanophenyl)-N′-[2-[[1-hydroxy-2-[4-(4-fluorophenyl)methyl)-1-piperidinyl]ethyl]phenyl]urea,

N-(3-cyanophenyl)-N′-[6-[1-hydroxy-2-[4-(4-fluorophenyl)methyl)-1-piperidinyl]ethyl]-1,3-benzodioxol-5-yl]urea,

N-(3-cyanophenyl)-N′-[2-[[2-[4-phenylmethyl)-1-piperidinyl]ethyl]phenyl]urea,

N-(3-cyanophenyl)-N′-[2-[[2-[4-(4-fluorophenyl)methyl)-1-piperidinyl)ethyl]phenyl]urea,

N-(3-methoxyphenyl)-N′-[2-[[2-[4-phenylmethyl)-1-piperidinyl]ethyl]phenyl]urea,

N-(3-methoxyphenyl)-N′-[2-[[2-[4-(4-fluorophenyl)methyl)-1-piperidinyl]ethyl]phenyl]urea,

N-(3-acetylphenyl)-N′-[2-[[2-[4-(4-fluorophenyl)methyl)-1-piperidinyl]ethyl]phenyl]urea,

N-(4-fluorophenyl)-N′-[2-[[2-[4-(4-fluorophenyl)methyl)-1-piperidinyl]ethyl]phenyl]urea,

N-(1-adamantyl)-N′-[2-[[2-[4-(4-fluorophenyl)methyl)-1-piperidinyl]ethyl]phenyl]urea,

1-[[6-[[[(3-cyanophenyl)amino]carbonyl]amino]-1,3-benzodioxol-5-yl]methyl]-1-methyl-4-(phenylmethyl]piperidiniumiodide,

1-[[3-hydroxy-6-[[[(3-cyanophenyl)amino]carbonyl]amino]-phenyl]methyl]-1-methyl-4-(phenylmethyl]piperidiniumchloride,

1-[[3-[(tetrahydropyran-2-yl)oxy]6-[[[(3-cyanophenyl)amino]carbonyl]amino]-phenyl]methyl]-1-methyl-4-(phenylmethyl]piperidiniumiodide,

N-(3-methoxyphenyl)-N′-[2-[[3-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

N-(4-methoxyphenyl)-N′-[4-[[3-(phenylmethyl)-1-piperidinyl]methyl]phenyl]urea,

Methyl-3-[[[(phenyl)amino]carbonyl]amino]-2-[[[3-phenylmethyl]-1-piperidinyl]methyl]-benzoate

Methyl-3-[[[(3-cyanophenyl)amino]carbonyl]amino]-2-[[[3-phenylmethyl]-1-piperidinyl]methyl]-benzoate

Methyl-3-[[[(3-methoxyphenyl)amino]carbonyl]amino]-2-[[[3-phenylmethyl]-1-piperidinyl]methyl]-benzoate

Methyl-3-[[[(3-acetylphenyl)amino]carbonyl]amino]-2-[[[3-phenylmethyl]-1-piperidinyl]methyl]-benzoate

Methyl-3-[[[(3-cyanophenyl)amino]carbonyl]amino]-2-[[[3-phenylmethyl]-1-piperidinyl]methyl]-benzoateHydrochloride

N-(3-methoxyphenyl)-N′-[2-[[1-hydroxy-2-[3-(phenylmethyl)-1-piperidinyl]ethyl]phenyl]urea,and

N-(3-methoxyphenyl)-N′-[2-[[2-(3-phenylmethyl)-1-piperidinyl]ethyl]phenyl]urea.

[11] In another embodiment, the present invention provides apharmaceutical composition, comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of thepresent invention.

[12] In another embodiment, the present invention provides a method formodulation of chemokine receptor activity comprising administering to apatient in need thereof a therapeutically effective amount of thecompounds of the present invention.

[13] In another embodiment, the present invention provides a method fortreating or preventing inflammatory diseases, comprising administeringto a patient in need thereof a therapeutically effective amount of acompound of the present invention.

[14] In another embodiment, the present invention provides a method fortreating or preventing asthma, comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of thepresent invention.

[15] In another embodiment, the present invention provides a novelmethod for the modulation of the chemokine receptor CCR-3 comprising theadministration of an effective amount of compounds of formula (I):

or stereoisomers or pharmaceutically acceptable salts thereof, wherein:

M is absent or selected from CH₂, CHR⁵, CHR¹³, CR¹³R¹³, and CR⁵R¹³;

Q is selected from CH₂, CHR⁵, CHR¹³, CR¹³R¹³, and CR⁵R¹³;

J, K, and L are independently selected from CH₂, CHR⁵, CHR⁶, CR⁶R⁶ andCR⁵R⁶;

with the proviso:

1) at least one of M, J, K, L, or Q contains an R⁵; and

2) when M is absent, J is selected from CH₂, CHR⁵, CHR¹³, and CR⁵R¹³;

Z is selected from O and S;

E is selected from:

ring A is phenyl or naphthyl;

R¹ and R² are independently selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(a);

R^(a), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(b)R^(b), (CH₂)_(r)OH, (CH₂)_(r)OR^(c), (CH₂)_(r)SH,(CH₂)_(r)SR^(c), (CH₂)_(r)C(O)R^(b), (CH₂)_(r)C(O)NR^(b)R^(b),(CH₂)_(r)NR^(b)C(O)R^(b), (CH₂)_(r)C(O)OR^(b), (CH₂)_(r)OC(O)R^(c),(CH₂)_(r)CH(═NR^(b))NR^(b)R^(b), (CH₂)_(r)NHC(═NR^(b))NR^(b)R^(b),(CH₂)_(r)S(O)_(p)R^(c), (CH₂)_(r)S(O)₂NR^(b)R^(b),(CH₂)_(r)NR^(b)S(O)₂R^(c), and (CH₂)_(r)phenyl;

R^(b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl;

R^(c), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl,and phenyl;

alternatively, R² and R³ join to form a 5, 6, or 7-membered ringsubstituted with 0-3 R^(a);

R³ is selected from a (CR³′R³″)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R¹⁵, and a (CR³′R³″)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R¹⁵;

R³′ and R³″, at each occurrence, are selected from H, C₁₋₆ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl;

R⁴ is absent, taken with the nitrogen to which it is attached to form anN-oxide, or selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(q)C(O)R^(4b),(CH₂)_(q)C(O)NR^(4a)R^(4a)′, (CH₂)_(q)C(O)OR^(4b), and a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(4c);

R^(4a) and R^(4a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl;

R^(4b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,(CH₂)_(r)C₃₋₆ cycloalkyl, C₂₋₈ alkynyl, and phenyl;

R^(4c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(4a)R^(4a)′, and (CH₂)_(r)phenyl;

alternatively, R⁴ joins with R⁷, R⁹, R¹¹ or R¹⁴ to form a 5, 6 or 7membered piperidinium spirocycle or pyrrolidinium spirocycle substitutedwith 0-3 R^(a);

R⁵ is selected from a (CR⁵′R⁵″)_(t)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R¹⁶ and a (CR⁵′R⁵″)_(t)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R¹⁶;

R⁵′ and R⁵″, at each occurrence, are selected from H, C₁₋₆ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl;

R⁶, at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CF₂)_(r)CF₃, CN,(CH₂)_(r)NR^(6a)R^(6a)′, (CH₂)_(r)OH, (CH₂)_(r)OR^(6b), (CH₂)_(r)SH,(CH₂)_(r)SR^(6b), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(6b),(CH₂)_(r)C(O)NR^(6a)R^(6a)′, (CH₂)_(r)NR^(6d)C(O)R^(6a),(CH₂)_(r)C(O)OR^(6b), (CH₂)_(r)OC(O)R^(6b), (CH₂)_(r)S(O)_(p)R^(6b),(CH₂)_(r)S(O)₂NR^(6a)R^(6a)′, (CH₂)_(r)NR^(6d)S(O)₂R^(6b), and(CH₂)_(t)phenyl substituted with 0-3 R^(6c);

R^(6a) and R^(6a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(6c);

R^(6b), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl substituted with 0-3 R^(6c);

R^(6c), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,(CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl, and (CH₂)_(r)NR^(6d)R^(6d);

R^(6d), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl;

with the proviso that when any of J, K, or L is CR⁶R⁶ and R⁶ is halogen,cyano, nitro, or bonded to the carbon to which it is attached through aheteroatom, the other R⁶ is not halogen, cyano, or bonded to the carbonto which it is attached through a heteroatom;

R⁷, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(q)OH, (CH₂)_(q)SH, (CH₂)_(q)OR^(7d), (CH₂)_(q)SR^(7d),(CH₂)_(q)NR^(7a)R^(7a)′, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(7b),(CH₂)_(r)C(O)NR^(7a)R^(7a)′, (CH₂)_(q)NR^(7a)C(O)R^(7a),(CH₂)_(q)NR^(7a)C(O)H, (CH₂)_(r)C(O)OR^(7b), (CH₂)_(q)OC(O)R^(7b),(CH₂)_(q)S(O)_(p)R^(7b), (CH₂)_(q)S(O)₂NR^(7a)R^(7a)′,(CH₂)_(q)NR^(7a)S(O)₂R^(7b), C₁₋₆ haloalkyl, a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(7c), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(7c);

R^(7a) and R^(7a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(7e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(7e);

R^(7b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2R^(7e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(7e);

R^(7c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(7f)R^(7f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(7b),(CH₂)_(r)C(O)NR^(7f)R^(7f), (CH₂)_(r)NR^(7f)C(O)R^(7a),(CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(7b),(CH₂)_(r)C(═NR^(7f))NR^(7f)R^(7f), (CH₂)_(r)S(O)_(p)R^(7b),(CH₂)_(r)NHC(═NR^(7f))NR^(7f)R^(7f), (CH₂)_(r)S(O)₂NR^(7f)R^(7f),(CH₂)_(r)NR^(7f)S(O)₂R^(7b), and (CH₂)_(r)phenyl substituted with 0-3R^(7e);

R^(7d), at each occurrence, is selected from C₁₋₆ alkyl substituted with0-3 R^(7e), alkenyl, alkynyl, and a C₃₋₁₀ carbocyclic residuesubstituted with 0-3 R^(7c);

R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;

R^(7f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl;

R⁸ is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(t)phenylsubstituted with 0-3 R^(8a);

R^(8a), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;

alternatively, R⁷ and R⁸ join to form C₃₋₇ cycloalkyl, or ═NR^(8b);

R^(8b) is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, OH, CN, and(CH₂)_(r)-phenyl;

R⁹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, F, Cl,Br, I, NO₂, CN, (CH₂)_(r)OH, (CH₂)_(r)SH, (CH₂)_(r)OR^(9d),(CH₂)_(r)SR^(9d), (CH₂)_(r)NR^(9a)R^(9a)′, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(9b), (CH₂)_(r)C(O)NR^(9a)R^(9a)′,(CH₂)_(r)NR^(9a)C(O)R^(9a), (CH₂)_(r)NR^(9a)C(O)H,(CH₂)_(r)NR^(9a)C(O)NHR^(9a), (CH₂)_(r)C(O)OR^(9b),(CH₂)_(r)OC(O)R^(9b), (CH₂)_(r)OC(O)NHR^(9a), (CH₂)_(r)S(O)_(p)R^(9b),(CH₂)_(r)S(O)₂NR^(9a)R^(9a)′, (CH₂)_(r)NR^(9a)S(O)₂R^(9b), C₁₋₆haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(9c), and a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(9c);

R^(9a) and R^(9a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(9e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(9e);

R^(9b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2R^(9e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(9e);

R^(9c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(9f)R^(9f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(9b),(CH₂)_(r)C(O)NR^(9f)R^(9f), (CH₂)_(r)NR^(9f)C(O)R^(9a),(CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(9b),(CH₂)_(r)C(═NR^(9f))NR^(9f)R^(9f), (CH₂)_(r)S(O)_(p)R^(9b),(CH₂)_(r)NHC(═NR^(9f))NR^(9f)R^(9f), (CH₂)_(r)S(O)₂NR^(9f)R^(9f),(CH₂)_(r)NR^(9f)S(O)₂R^(9b), and (CH₂)_(r)phenyl substituted with 0-3R^(9e);

R^(9d), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(9c),and a 5-6 membered heterocyclic system containing 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R^(9c);

R^(9e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(9f)R^(9f), and (CH₂)_(r)phenyl;

R^(9f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl;

R¹⁰, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, F, Cl,Br, I, NO₂, CN, (CH₂)_(r)OH, (CH₂)_(r)OR^(10d), (CH₂)_(r)SR^(10d),(CH₂)_(r)NR^(10a)R^(10a)′, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(10b),(CH₂)_(r)C(O)NR^(10a)R^(10a)′, (CH₂)_(r)NR^(10a)C(O)R^(10a),(CH₂)_(r)NR^(10a)C(O)H, (CH₂)_(r)C(O)OR^(10b), (CH₂)_(r)OC(O)R^(10b),(CH₂)_(r)S(O)_(p)R^(10b), (CH₂)_(r)S(O)₂NR^(10a)R^(10a)′,(CH₂)_(r)NR^(10a)S(O)₂R^(10b), C₁₋₆ haloalkyl, a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(10c), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(10c);

R^(10a) and R^(10a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(10e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(10e);

R^(10b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2R^(10e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(10e);

R^(10c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(10f)R^(10f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(10b),(CH₂)_(r)C(O)NR^(10f)R^(10f), (CH₂)_(r)NR^(10f)C(O)R^(10a),(CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(10b),(CH₂)_(r)C(═NR^(10f))NR^(10f)R^(10f), (CH₂)_(r)S(O)_(p)R^(10b),(CH₂)_(r)NHC(═NR^(10f))NR^(10f)R^(10f), (CH₂)_(r)S(O)₂NR^(10f)R^(10f),(CH₂)_(r)NR^(10f)S(O)₂R^(10b), and (CH₂)_(r)phenyl substituted with 0-3R^(10e);

R^(10d), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(10c),and a 5-6 membered heterocyclic system containing 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R^(10c);

R^(10e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(10f)R^(10f), and (CH₂)_(r)phenyl;

R^(10f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆cycloalkyl;

alternatively, R⁹ and R¹⁰ join to form C₃₋₇ cycloalkyl, 5-6-memberedcyclic ketal or ═O;

with the proviso that when R¹⁰ is halogen, cyano, nitro, or bonded tothe carbon to which it is attached through a heteroatom, R⁹ is nothalogen, cyano, or bonded to the carbon to which it is attached througha heteroatom;

R¹¹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(q)OH, (CH₂)_(q)SH, (CH₂)_(q)OR^(11d), (CH₂)_(q)SR^(11d),(CH₂)_(q)NR^(11a)R^(11a)′, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(11b),(CH₂)_(r)C(O)NR^(11a)R^(11a)′, (CH₂)_(q)NR^(11a)C(O)R^(11a),(CH₂)_(q)NR^(11a)C(O)NHR^(11a), (CH₂)_(r)C(O)OR^(11b),(CH₂)_(q)OC(O)R^(11b), (CH₂)_(q)S(O)_(p)R^(11b),(CH₂)_(q)S(O)₂NR^(11a)R^(11a)′, (CH₂)_(q)NR^(11a)S(O)₂R^(11b), C₁₋₆haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(11c), and a (CH₂)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(11c);

R^(11a) and R^(11a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(11e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(11e);

R^(11b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2R^(11e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e);

R^(11c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF2)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(11f)R^(11f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(11b),(CH₂)_(r)C(O)NR^(11f)R^(11f), (CH₂)_(r)NR^(11f)C(O)R^(11a),(CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(11b),(CH₂)_(r)C(═NR^(11f))NR^(11f)R^(11f),(CH₂)_(r)NHC(═NR^(11f))NR^(11f)R^(11f), (CH₂)_(r)S(O)_(p)R^(11b),(CH₂)_(r)S(O)₂NR^(11f)R^(11f), (CH₂)_(r)NR^(11f)S(O)₂R^(11b), and(CH₂)_(r)phenyl substituted with 0-3 R^(11e);

R^(11d), at each occurrence, is selected from C₁₋₆ alkyl substitutedwith 0-3 R^(11e), C₂₋₆ alkenyl, C₂₋₆ alkynyl, and a C₃₋₁₀ carbocyclicresidue substituted with 0-3 R^(11c);

R^(11e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl;

R^(11f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl;

R¹² is selected from H, C₁₋₆ alkyl, (CH₂)_(q)OH, (CH₂)_(r)C₃₋₆cycloalkyl, and (CH₂)tphenyl substituted with 0-3 R^(12a);

R^(12a), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(9f)R^(9f), and (CH₂)_(r)phenyl;

alternatively, R¹¹ and R¹² join to form C₃₋₇ cycloalkyl;

R¹³, at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C₃₋₆ cycloalkyl, (CF₂)_(w)CF₃, (CH₂)_(r)NR^(13a)R^(13a)′,(CH₂)_(r)OH, (CH₂)_(r)OR^(13b), (CH₂)_(r)SH, (CH₂)_(r)SR^(13b),(CH₂)_(w)C(O)OH, (CH₂)_(w)C(O)R^(13b), (CH₂)_(w)C(O)NR^(13a)R^(13a)′,(CH₂)_(r)NR^(13d)C(O)R^(13a), (CH₂)_(w)C(O)OR^(13b),(CH₂)_(r)OC(O)R^(13b), (CH₂)_(w)S(O)_(p)R^(13b),(CH₂)_(w)S(O)₂NR^(13a)R^(13a)′, (CH₂)NR^(13d)S(O)₂R^(13b), and(CH₂)_(w)-phenyl substituted with 0-3 R^(13c);

R^(13a) and R^(13a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(13c);

R^(13b), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl substituted with 0-3 R^(13c);

R^(13c), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,(CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl, and (CH₂)_(r)NR^(13d)R^(13d);

R^(13d), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl;

R¹⁴, at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(14a)R^(14a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(14d),(CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(14d),(CHR′)_(r)C(O)OH, (CHR′)_(r)C(O) (CHR′)_(r)R^(14b),(CHR′)_(r)C(O)NR^(14a)R^(14a)′, (CHR′)_(r)NR^(14f)C(O)(CHR′)_(r)R^(14b), (CHR′)_(r)C(O)O(CHR′)_(r)R^(14d),(CHR′)_(r)OC(O)(CHR′)_(r)R^(14b),(CHR′)_(r)C(═NR^(14f))NR^(14a)R^(14a)′,(CHR′)_(r)NHC(═NR^(14f))NR^(14f)R^(14f),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(14b), (CHR′)_(r)S(O)₂NR^(14a)R^(14a)′,(CHR′)_(r)NR^(14f)S(O)₂(CHR′)_(r)R^(14b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(14e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e), or two R¹⁴ substituents onadjacent atoms on ring A form to join a 5-6 membered heterocyclic systemcontaining 1-3 heteroatoms selected from N, O, and S substituted with0-2 R^(15e);

alternatively, R¹⁴ joins with R⁴ to form a 5, 6 or 7 memberedpiperidinium spirocycle or pyrrolidinium spirocycle fused to ring A, thespirocycle substituted with 0-3 R^(a);

R′, at each occurrence, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substitutedwith R^(14e);

R^(14a) and R^(14a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(14e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(14e);

R^(14b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3R^(14e), and (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(14e);

R^(14d), at each occurrence, is selected from C₂₋₈ alkenyl, C₂₋₈alkynyl, C₁₋₆ alkyl substituted with 0-3 R^(14e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(14e), and a (CH₂)_(r)5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(14e);

R^(14e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(14f)R^(14f), and (CH₂)_(r)phenyl;

R^(14f), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl;

R¹⁵, at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(15a)R^(15a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(15d),(CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(15d),(CHR′)_(r)C(O)OH, (CHR′)_(r)C(O) (CHR′)_(r)R^(15b),(CHR′)_(r)C(O)NR^(15a)R^(15a)′, (CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b), (CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b), (CHR′)_(r)C(═NR^(15f))NR^(15a)R^(15a)′,(CHR′)_(r)NHC(═NR^(15f))NR^(15f)R^(15f),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)₂NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)S(O)₂ (CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e);

R^(15a) and R^(15a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(15e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(15e);

R^(15b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3R^(15e), and (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);

R^(15d), at each occurrence, is selected from C₂₋₈ alkenyl, C₂₋₈alkynyl, C₁₋₆ alkyl substituted with 0-3 R^(15e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(15e), and a (CH₂)_(r)5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(15e);

R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(15f)R^(15f), and (CH₂)_(r)phenyl;

R^(15f), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl;

R¹⁶, at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(16a)R^(16a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(16d),(CHR′)_(r)SH, (CHR′)_(r)C(O) H, (CHR′)_(r)S(CHR′)_(r)R^(16d),(CHR′)_(r)C(O)OH, (CHR′)_(r)C(O) (CHR′)_(r)R^(16b),(CHR′)_(r)C(O)NR^(16a)R^(16a)′, (CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b), (CHR′)_(r)C(O)O(CHR′)_(r)R^(16d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(16b), (CHR′)_(r)C(═NR^(16f))NR^(16a)R^(16a)′,(CHR′)_(r)NHC(═NR^(16f))NR^(16f)R^(16f),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂NR^(16a)R^(16a)′,(CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and(CHR′)_(r)phenyl substituted with 0-3 R^(16e);

R^(16a) and R^(16a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(16e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(16e);

R^(16b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3R^(16e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(16e);

R^(16d), at each occurrence, is selected from C₂₋₈ alkenyl, C₂₋₈alkynyl, C₁₋₆ alkyl substituted with 0-3 R^(16e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(16e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(16e);

R^(16e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(16f)R^(16f), and (CH₂)_(r)phenyl;

R^(16f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl, and phenyl;

g is selected from 0, 1, 2, 3, and 4;

t is selected from 1 and 2;

w is selected from 0 and 1;

r is selected from 0, 1, 2, 3, 4, and 5;

q is selected from 1, 2, 3, 4, and 5; and

p is selected from 0, 1, 2, and 3.

[16] In a preferred embodiment, the present invention provides a novelmethod for the modulation of the chemokine receptor CCR-3 comprising theadministration of an effective amount of compounds of formula (I),wherein:

E is selected from:

R⁴ is absent, taken with the nitrogen to which it is attached to form anN-oxide, or selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and(CH₂)_(r)-phenyl substituted with 0-3 R^(4c);

R^(4c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(4a)R^(4a)′, and (CH₂)_(r)phenyl;

alternatively, R⁴ joins with R⁷,R⁹ or R¹⁴ to form a 5, 6 or 7 memberedpiperidinium spirocycle substituted with 0-3 R^(a);

R¹ and R² are independently selected from H and C₁₋₄ alkyl;

R⁶, at each occurrence, is selected from C₁₋₄ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CF₂)_(r)CF₃, CN, (CH₂)_(r)OH,(CH₂)_(r)OR^(6b), (CH₂)_(r)C(O)R^(6b), (CH₂)_(r)C(O)NR^(6a)R^(6a)′,(CH₂)_(r)NR^(6d)C(O)R^(6a), and (CH₂)_(t)phenyl substituted with 0-3R^(6c);

R^(6a) and R^(6a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(6c);

R^(6b), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl substituted with 0-3 R^(6c);

R⁶c, at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl,Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH,(CH₂)_(r)SC₁₋₅ alkyl, and (CH₂)_(r)NR^(6d)R^(6d);

R^(6d), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl;

R⁷, is selected from H, C₁₋₃ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl,(CH₂)_(q)OH, (CH₂)_(q)OR^(7d), (CH₂)_(q)NR^(7a)R^(7a)′,(CH₂)_(r)C(O)R^(7b), (CH₂)_(r)C(O)NR^(7a)R^(7a)′,(CH₂)_(q)NR^(7a)C(O)R^(7a), C₁₋₆ haloalkyl, (CH₂)_(r)phenyl with 0-2R^(7c);

R^(7a) and R^(7a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)phenyl substituted with 0-3 R^(7e);

R^(7b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(r)phenyl substituted with0-3 R^(7e);

R⁷c, at each occurrence, is selected from C₁₋₄ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN,(CH₂)_(r)NR^(7f)R^(7f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)C(O)R^(7b), (CH₂)_(r)C(O)NR^(7f)R^(7f),(CH₂)_(r)NR^(7f)C(O)R^(7a), (CH₂)_(r)S(O)_(p)R^(7b),(CH₂)_(r)S(O)₂NR^(7f)R^(7f), (CH₂)_(r)NR^(7f)S(O)₂R^(7b), and(CH₂)_(r)phenyl substituted with 0-2 R^(7e);

R^(7d), at each occurrence, is selected from C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, (CH₂)_(r)phenyl substituted with 0-3 R^(7e);

R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;

R^(7f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆cycloalkyl;

R⁸ is H or joins with R⁷ to form C₃₋₇ cycloalkyl or ═NR^(8b);

R¹¹, is selected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl,(CH₂)_(q)OH, (CH₂)_(q)OR^(11d), (CH₂)_(q)NR^(11a)R^(11a)′,(CH₂)_(r)C(O)R^(11b), (CH₂)_(r)C(O)NR^(11a)R^(11a)′,(CH₂)_(q)NR^(11a)C(O)R^(11a), C₁₋₆ haloalkyl, (CH₂)_(r)phenyl with 0-2R^(11c), (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R¹⁵;

R^(11a) and R^(11a)′, at each occurrence, are selected from H, C₁₋₆alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)phenyl substituted with 0-3R^(11e);

R^(11b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(r)phenyl substituted with0-3 R^(11e);

R^(11c), at each occurrence, is selected from C₁₋₄ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(11f)R^(11f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)C(O)R^(11b), (CH₂)_(r)C(O)NR^(11f)R^(11f),(CH₂)_(r)NR^(11f)C(O)R^(11a), (CH₂)_(r)S(O)_(p)R^(11b),(CH₂)_(r)S(O)₂NR^(11f)R^(11f), (CH₂)_(r)NR^(11f)S(O)₂R^(11b), and(CH₂)_(r)phenyl substituted with 0-2 R^(11e);

R^(11d), at each occurrence, is selected from C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, (CH₂)_(r)phenyl substituted with 0-3 R^(11e);

R^(11e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl;

R^(11f), at each occurrence, is selected from H, C₁₋₅ alkyl and C₃₋₆cycloalkyl;

R¹² is H or joins with R¹¹ to form C₃₋₇ cycloalkyl;

R¹³, at each occurrence, is selected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl,(CH₂)NR^(13a)R^(13a)′, (CH₂)OH, (CH₂)OR^(13b), (CH₂)_(w)C(O)R^(13b),(CH₂)_(w)C(O)NR^(13a)R^(13a)′, (CH₂)NR^(13d)C(O)R^(13a),(CH₂)_(w)S(O)₂NR^(13a)R^(13a)′, (CH₂)NR^(13d)S(O)₂R^(13b), and(CH₂)_(w)-phenyl substituted with 0-3 R^(13c);

R^(13a) and R^(13a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(13c);

R^(13b), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl substituted with 0-3 R^(13c);

R^(13c), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,(CH₂)_(r)OH, and (CH₂)_(r)NR^(13d)R^(13d);

R^(13d), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl;

q is selected from 1, 2, and 3; and

r is selected from 0, 1, 2, and 3.

[17] In a more preferred embodiment, the present invention provides anovel method for the modulation of the chemokine receptor CCR-3comprising the administration of an effective amount of compounds offormula (I), wherein:

ring A is selected from:

R³ is selected from a (CR³′H)_(r)-carbocyclic residue substituted with0-5 R¹⁵, wherein the carbocyclic residue is selected from phenyl, C₃₋₆cycloalkyl, naphthyl, and adamantyl; and a (CR³′H)_(r)-heterocyclicsystem substituted with 0-4 R¹⁵, wherein the heterocyclic system isselected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl,benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl,benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl,indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl,pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl,thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and

R⁵ is selected from (CR⁵′H)_(t)-phenyl substituted with 0-5 R¹⁶; and a(CR⁵′H)_(t)-heterocyclic system substituted with 0-3 R¹⁶, wherein theheterocyclic system is selected from pyridinyl, thiophenyl, furanyl,indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl,imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl,1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl.

[18] In an even more preferred embodiment, the present inventionprovides a novel method for the modulation of the chemokine receptorCCR-3 comprising the administration of an effective amount of compoundsof formula (I-i), wherein the compound of formula (I-i) is:

with the proviso that at least one of J, K or L contains an R⁵;

R¹⁶, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(16a)R^(16a)′, NO₂, CN, OH,(CH₂)_(r)OR^(16d), (CH₂)_(r)C(O)R^(16b), (CH₂)_(r)C(O)NR^(16a)R^(16a)′,(CH₂)_(r)NR^(16f)C(O)R^(16b), (CH₂)_(r)S(O)_(p)R^(16b),(CH₂)_(r)S(O)₂NR^(16a)R^(16a)′, (CH₂)_(r)NR^(16f)S(O)₂R^(16b), and(CH₂)_(r)phenyl substituted with 0-3 R^(16e);

R^(16a) and R^(16a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3R^(16e);

R^(16b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(16e);

R^(16d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(16e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and

R^(16f), at each occurrence, is selected from H, and C₁₋₅ alkyl.

[19] In an another even more preferred embodiment, the present inventionprovides a novel method for the modulation of the chemokine receptorCCR-3 comprising the administration of an effective amount of compoundsof formula (I-ii), wherein (I-ii) is:

with the proviso that at least one of K or L contains an R⁵;

R¹⁶, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(16a)R^(16a)′, NO₂, CN, OH,(CH₂)_(r)OR^(16d), (CH₂)_(r)C(O)R^(16b), (CH₂)_(r)C(O)NR^(16a)R^(16a)′,(CH₂)_(r)NR^(16f)C(O)R^(16b), (CH₂)_(r)S(O)_(p)R^(16b),(CH₂)_(r)S(O)₂NR^(16a)R^(16a)′, (CH₂)_(r)NR^(16f)S(O)₂R^(16b), and(CH₂)_(r)phenyl substituted with 0-3 R^(16e);

R^(16a) and R^(16a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3R^(16e);

R^(16b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(16e);

R^(16d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(16e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and

R^(16f), at each occurrence, is selected from H, and C₁₋₅ alkyl.

[20] In a preferred embodiment, the present invention provides a novelmethod for the modulation of the chemokine receptor CCR-3 comprising theadministration of an effective amount of compounds of formula (I-i),wherein:

R⁵ is CH₂phenyl substituted with 0-3 R¹⁶;

R⁹, is selected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, F, Cl, CN,(CH₂)_(r)OH, (CH₂)_(r)OR^(9d), (CH₂)_(r)NR^(9a)R^(9a)′,(CH₂)_(r)OC(O)NHR^(9a), (CH₂)_(r)phenyl substituted with 0-5 R^(9e), anda heterocyclic system substituted with 0-2 R^(9e), wherein theheterocyclic system is selected from pyridyl, thiophenyl, furanyl,oxazolyl, and thiazolyl;

R^(9a) and R^(9a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(9e);

R^(9d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(9e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl;

R¹⁰ is selected from H, C₁₋₅ alkyl, OH, and CH₂OH;

alternatively, R⁹ and R¹⁰ join to form C₃₋₇ cycloalkyl, 5-6-memberedcyclic ketal or ═O;

with the proviso that when R¹⁰ is halogen, cyano, nitro, or bonded tothe carbon to which it is attached through a heteroatom, R⁹ is nothalogen, cyano, or bonded to the carbon to which it is attached througha heteroatom;

R¹¹ is selected from H, C₁₋₈ alkyl, (CH₂)_(r)phenyl substituted with 0-5R^(11e), and a (CH₂)_(r)-heterocyclic system substituted with 0-2R^(11e), wherein the heterocyclic system is selected from pyridinyl,thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl,1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl; and

R^(11e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl;

R¹² is H;

alternatively, R¹¹ and R¹² join to form C₃₋₇ cycloalkyl;

R¹⁴, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(14a)R^(14a)′, NO₂, CN, OH,(CH₂)_(r)OR^(14d), (CH₂)_(r)C(O)R^(14b), (CH₂)_(r)C(O)NR^(14a)R^(14a)′,(CH₂)_(r)NR^(14f)C(O)R^(14b), (CH₂)_(r)S(O)_(p)R^(14b),(CH₂)_(r)S(O)₂NR^(14a)R^(14a)′, (CH₂)_(r)NR^(14f)S(O)₂R^(14b),(CH₂)_(r)phenyl substituted with 0-3 R^(14e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e), or two R¹⁴ substituents onadjacent atoms on ring A form to join a 5-6 membered heterocyclic systemcontaining 1-3 heteroatoms selected from N, O, and S substituted with0-2 R^(15e);

R^(14a) and R^(14a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3R^(14e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);

R^(14b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(14e);

R^(14d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(14e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂,(CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and

R^(14f), at each occurrence, is selected from H, and C₁₋₅ alkyl; and

r is selected from 0, 1, and 2.

[21] In a preferred embodiment, the present invention provides a novelmethod for the modulation of the chemokine receptor CCR-3 comprising theadministration of an effective amount of compounds of formula (I-ii),wherein:

R⁵ is CH₂phenyl substituted with 0-3 R¹⁶;

R⁹, is selected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, F, Cl, CN,(CH₂)_(r)OH, (CH₂)_(r)OR^(9d), (CH₂)_(r)NR^(9a)R^(9a)′,(CH₂)_(r)OC(O)NHR^(9a), (CH₂)_(r)phenyl substituted with 0-5 R^(9e), anda heterocyclic system substituted with 0-2 R^(9e), wherein theheterocyclic system is selected from pyridyl, thiophenyl, furanyl,oxazolyl, and thiazolyl;

R^(9a) and R^(9a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(9e);

R^(9d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(9e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl;

R¹⁰ is selected from H, C₁₋₈ alkyl, OH, and CH₂OH;

alternatively, R⁹ and R¹⁰ join to form C₃₋₇ cycloalkyl, 5-6-memberedcyclic ketal or ═O;

with the proviso that when R¹⁰ is halogen, cyano, nitro, or bonded tothe carbon to which it is attached through a heteroatom, R⁹ is nothalogen, cyano, or bonded to the carbon to which it is attached througha heteroatom;

R¹¹ is selected from H, C₁₋₈ alkyl, (CH₂)_(r)phenyl substituted with 0-5R^(11e), and a (CH₂)_(r)-heterocyclic system substituted with 0-2R^(11e), wherein the heterocyclic system is selected from pyridinyl,thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl,1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl; and

R^(11e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl;

R¹² is H;

alternatively, R¹¹ and R¹² join to form C₃₋₇ cycloalkyl;

R¹⁴, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(14a)R^(14a)′, NO₂, CN, OH,(CH₂)_(r)OR^(14d), (CH₂)_(r)C(O)R^(14b), (CH₂)_(r)C(O)NR^(14a)R^(14a)′,(CH₂)_(r)NR^(14f)C(O)R^(14b), (CH₂)_(r)S(O)_(p)R^(14b),(CH₂)_(r)S(O)₂NR^(14a)R^(14a)′, (CH₂)_(r)NR^(14f)S(O)₂R^(14b),(CH₂)_(r)phenyl substituted with 0-3 R^(14e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e), or two R¹⁴ substituents onadjacent atoms on ring A form to join a 5-6 membered heterocyclic systemcontaining 1-3 heteroatoms selected from N, O, and S substituted with0-2 R^(15e);

R^(14a) and R^(14a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3R^(14e);

R^(14b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(14e);

R^(14d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(14e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl;

R^(14f), at each occurrence, is selected from H, and C₁₋₅ alkyl; and

r is selected from 0, 1, and 2.

[22] In a more preferred embodiment, the present invention provides anovel method for the modulation of the chemokine receptor CCR-3comprising the administration of an effective amount of compounds offormula (I-i), wherein:

J is selected from CH₂ and CHR⁵;

K is selected from CH₂ and CHR⁵;

L is selected from CH₂ and CHR⁵;

with the proviso that at least one of J, K or L is CHR⁵;

R³ is a C₃₋₁₀ carbocyclic residue substituted with 0-3 R¹⁵, wherein thecarbocyclic residue is selected from cyclopropyl, cyclopentyl,cyclohexyl, phenyl, naphthyl and adamantyl, and a(CR³′H)_(r)-heterocyclic system substituted with 0-3 R¹⁵, wherein theheterocyclic system is selected from pyridinyl, thiophenyl, furanyl,indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl,imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl,piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl,thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and

R¹⁵, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(15a)R^(15a)′, NO₂, CN, OH,(CH₂)_(r)OR^(15d), (CH₂)_(r)C(O)R^(15b), (CH₂)_(r)C(O)NR^(15a)R^(15a)′,(CH₂)_(r)NR^(15f)C(O)R^(15b), (CH₂)_(r)S(O)_(p)R^(15b),(CH₂)_(r)S(O)₂NR^(15a)R^(15a)′, (CH₂)_(r)NR^(15f)S(O)₂R^(15b),(CH₂)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e);

R^(15a) and R^(15a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3R^(15e);

R^(15b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(15e).

R^(15d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and

R¹⁵f, at each occurrence, is selected from H, and C₁₋₅ alkyl.

[23] In a more preferred embodiment, the present invention provides anovel method for the modulation of the chemokine receptor CCR-3comprising the administration of an effective amount of compounds offormula (I-ii), wherein:

K is selected from CH₂ and CHR⁵;

L is selected from CH₂ and CHR⁵;

with the proviso that at least one of K or L is CHR⁵;

R³ is a C₃₋₁₀ carbocyclic residue substituted with 0-3 R¹⁵, wherein thecarbocyclic residue is selected from cyclopropyl, cyclopentyl,cyclohexyl, phenyl, naphthyl and adamantyl, and a(CR³′H)_(r)-heterocyclic system substituted with 0-3 R¹⁵, wherein theheterocyclic system is selected from pyridinyl, thiophenyl, furanyl,indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl,imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl,piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl,thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and

R¹⁵, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(15a)R^(15a)′, NO₂, CN, OH,(CH₂)_(r)OR^(15d), (CH₂)_(r)C(O)R^(15b), (CH₂)_(r)C(O)NR^(15a)R^(15a)′,(CH₂)_(r)NR^(15f)C(O)R^(15b), (CH₂)_(r)S(O)_(p)R^(15b),(CH₂)_(r)S(O)₂NR^(15a)R^(15a)′, (CH₂)_(r)NR^(15f)S(O)₂R^(15b), and(CH₂)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e);

R^(15a) and R^(15a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3R^(15e);

R^(15b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(15e);

R^(15d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and

R¹⁵f, at each occurrence, is selected from H and C₁₋₅ alkyl.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of the present invention.

In another embodiment, the present invention provides a method formodulation of chemokine receptor activity comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof the present invention.

In a preferred embodiment, the present invention provides a method formodulation of chemokine receptor activity comprising contacting a CCR3receptor with an effective inhibitory amount of a compound of thepresent invention.

In another embodiment, the present invention provides a method fortreating inflammatory disorders comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of thepresent invention

In another embodiment, the present invention provides a method fortreating or preventing disorders selected from asthma, allergicrhinitis, atopic dermatitis, inflammatory bowel diseases, idiopathicpulmonary fibrosis, bullous pemphigoid, helminthic parasitic infections,allergic colitis, eczema, conjunctivitis, transplantation, familialeosinophilia, eosinophilic cellulitis, eosinophilic pneumonias,eosinophilic fasciitis, eosinophilic gastroenteritis, drug inducedeosinophilia, HIV infection, cystic fibrosis, Churg-Strauss syndrome,lymphoma, Hodgkin's disease, and colonic carcinoma.

In a preferred embodiment, the present invention provides a method fortreating or preventing disorders selected from asthma, allergicrhinitis, atopic dermatitis, and inflammatory bowel diseases.

In a more preferred embodiment, the present invention provides a methodfor treating or preventing disorders wherein the disorder is asthma.

Definitions

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced.

When any variable (e.g., R^(a)) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R^(a), then saidgroup may optionally be substituted with up to two R^(a) groups andR^(a) at each occurrence is selected independently from the definitionof R^(a). Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “C₁₋₈ alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, examples of which include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, pentyl, and hexyl. C₁₋₈ alkyl, is intended toinclude C₁, C₂, C₃, C₄, C₅, C₆, C₇, and C₈ alkyl groups. “Alkenyl” isintended to include hydrocarbon chains of either a straight or branchedconfiguration and one or more unsaturated carbon-carbon bonds which mayoccur in any stable point along the chain, such as ethenyl, propenyl,and the like. “Alkynyl” is intended to include hydrocarbon chains ofeither a straight or branched configuration and one or more unsaturatedtriple carbon-carbon bonds which may occur in any stable point along thechain, such as ethynyl, propynyl, and the like. “C₃₋₆ cycloalkyl” isintended to include saturated ring groups having the specified number ofcarbon atoms in the ring, including mono-, bi-, or poly-cyclic ringsystems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl in the case of C₇ cycloalkyl. C₃₋₆ cycloalkyl, is intendedto include C₃, C₄, C₅, and C₆ cycloalkyl groups

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups, for example CF₃,having the specified number of carbon atoms, substituted with 1 or morehalogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)).

The compounds of Formula I can also be quaternized by standardtechniques such as alkylation of the piperidine or pyrrolidine with analkyl halide to yield quaternary piperidinium salt products of FormulaI. Such quaternary piperidinium salts would include a counterion. Asused herein, “counterion” is used to represent a small, negativelycharged species such as chloride, bromide, hydroxide, acetate, sulfate,and the like.

As used herein, the term “piperidinium spirocycle or pyrrolidiniumspirocycle” is intented to mean a stable spirocycle ring system, inwhich the two rings form a quarternary nitrogene at the ring junction.

As used herein, the term “5-6-membered cyclic ketal” is intended to mean2,2-disubstituted 1,3-dioxolane or 2,2-disubstituted 1,3-dioxane andtheir derivatives.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7,8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which maybe saturated, partially unsaturated, or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,;[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term “heterocycle” or “heterocyclic system” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated,partially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, NH, O and S and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring. The nitrogen and sulfur heteroatoms may optionally beoxidized. The heterocyclic ring may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. If specificallynoted, a nitrogen in the heterocycle may optionally be quaternized. Itis preferred that when the total number of S and O atoms in theheterocycle exceeds 1, then these heteroatoms are not adjacent to oneanother. As used herein, the term “aromatic heterocyclic system” isintended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic aromatic ring which consists ofcarbon atoms and from 1 to 4 heteroatoms independently selected from thegroup consisting of N, O and S.

Examples of heterocycles include, but are not limited to, 1H-indazole,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, tetrazolyl, and xanthenyl. Preferred heterocyclesinclude, but are not limited to, pyridinyl, thiophenyl, furanyl,indazolyl, benzothiazolyl, benzimidazolyl, benzothiaphenyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl,imidazolyl, indolyl, isoidolyl, piperidinyl, piperidonyl, 4-piperidonyl,piperonyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl,thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl. Also included are fusedring and spiro compounds containing, for example, the aboveheterocycles.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc .. . ) the compounds of the present invention may be delivered in prodrugform. Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same. “prodrugs”are intended to include anycovalently bonded carriers which release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate derivatives of alcoholand amine functional groups in the compounds of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

Synthesis

The compounds of Formula I can be prepared using the reactions andtechniques described below. The reactions are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. It will be understood by those skilledin the art of organic synthesis that the functionality present on themolecule should be consistent with the transformations proposed. Thiswill sometimes require a judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention. It will also berecognized that another major consideration in the planning of anysynthetic route in this field is the judicious choice of the protectinggroup used for protection of the reactive functional groups present inthe compounds described in this invention. An authoritative accountdescribing the many alternatives to the trained practitioner is Greeneand Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).

Generally, compounds described in the scope of this patent applicationcan be synthesized by the route described in Scheme 1. The appropriatelysubstituted pyrrolidine (n=0) or piperidine (n=1) 1 is alkylated by aN-protected alkylhalide (halide=Cl, Br, I), mesylate, tosylate ortriflate, 2, (where E represents a linkage described within the scope ofthis application in its fully elaborated form with the appropriateprotecting groups as understood by one skilled in the art or in aprecursor form which can be later elaborated into its final form bymethods familiar to one skilled in the art) with or without base or anacid scavenger to yield the piperidinyl- or pyrrolidinylalkyl protectedamine 3. If the halide is not I, then KI can also be added to facilitatethe displacement, provided the solvent is suitable, such as an alcohol,2-butanone, DMF or DMSO, amongst others. The displacement can beperformed at room temperature to the reflux temperature of the solvent.The protecting group is subsequently removed to yield amine 4.Protecting groups include phthalimide which can be removed by hydrazine,a reaction familiar to one skilled in the art; bis-BOC which can beremoved by either TFA or HCl dissolved in a suitable solvent, bothprocedures being familiar to one skilled in the art; a nitro groupinstead of an amine which can be reduced to yield an amine by conditionsfamiliar to one skilled in the art; 2,4-dimethyl pyrrole (S. P.Breukelman, et al. J. Chem. Soc. Perkin Trans. I, 1984, 2801);N-1,1,4,4-Tetramethyl-disilylazacyclopentane (STABASE) (S. Djuric, J.Venit, and P. Magnus Tet. Lett 1981, 22, 1787) and other protectinggroups. Reaction with an isocyanate or isothiocyanate 5 (Z═O,S) yieldsurea or thiourea 6. Reaction with a chloroformate or chlorothioformate 7(Z═O,S) such as o-, p-nitrophenyl-chloroformate or phenylchloroformate(or their thiocarbonyl equivalents), followed by diplacement with anamine 9, also yields the corresponding urea or thiourea 6. Likewise,reaction of carbamate 8 (X═H, or 2- or 4-NO2) with disubstituted amine10 yields trisubstituted urea or thiourea 12. Reaction of the amine 4with an N,N-disubstituted carbamoyl chloride 11 (or its thiocarbonylequivalent) yields the corresponding N,N-disubstituted urea or thiourea12. Amine 4 can also be reductively aminated to yield 13 by conditionsfamiliar to one skilled in the art and by the following conditions:Abdel-Magid, A. F., et al. Tet. Lett. 1990, 31, (39) 5595-5598. Thissecondary amine can subsequently be reacted with isocyanates orisothiocyanates to yield trisubstituted ureas 14 or with carbamoylchlorides to yield tetrasubstituted ureas 15.

One can also convert amine 4 into an isocyanate, isothiocyanate,carbamoyl chloride or its thiocarbonyl equivalent (isocyanate:Nowakowski, J. J Prakt. Chem/Chem-Ztg 1996, 338 (7), 667-671; Knoelker,H.-J. et al., Angew. Chem. 1995, 107 (22), 2746-2749; Nowick, J. S. etal., J. Org. Chem. 1996, 61 (11), 3929-3934; Staab, H. A.; Benz, W.;Angew Chem 1961, 73; isothiocyanate: Strekowski L. et al., J.Heterocycl. Chem. 1996, 33 (6), 1685-1688; Kutschy, Pet al., Synlett.1997, (3), 289-290) carbamoyl chloride: Hintze, F.; Hoppe, D.; Synthesis(1992) 12, 1216-1218; thiocarbamoyl chloride: Ried, W.; Hillenbrand, H.;Oertel, G.; Justus Liebigs Ann Chem 1954, 590) (these reactions are notshown in Scheme 1). These isocyanates, isothiocyantes, carbamoylchlorides or thiocarbamoyl chlorides can then be reacted with R²R³NH toyield di- or trisubstituted ureas or thioureas 12. An additional ureaforming reaction involves the reaction of carbonyldiimidazole (CDI)(Romine, J. L.; Martin, S. W.; Meanwell, N. A.; Epperson, J. R.;Synthesis 1994 (8), 846-850) with 4 followed by reaction of theintermediate imidazolide with 9 or in the reversed sequence (9+CDI,followed by 4). Activation of imidazolide intermediates also facilitatesurea formation (Bailey, R. A., et al., Tet. Lett. 1998, 39, 6267-6270).One can also use 13 and 10 with CDI. The urea forming reactions are donein a non-hydroxylic inert solvent such as THF, toluene, DMF, etc., atroom temperature to the reflux temperature of the solvent and can employthe use of an acid scavenger or base when necessary such as carbonateand bicarbonate salts, triethylamine, DBU, Hunigs base, DMAP, etc.

Substituted pyrrolidines and piperidines 1 can either be obtainedcommercially or be prepared as shown in Scheme 2. Commercially availableN-benzylpiperid-3-one 16 can be debenzylated and protected with a BOCgroup employing reactions familiar to one skilled in the art. SubsequentWittig reaction followed by reduction and deprotection yields piperidine20 employing reactions familiar to one skilled in the art. Substitutedpyrrolidines may be made by a similar reaction sequence. Other isomersand analogs around the piperidine ring can also be made by a similarreaction sequence. Chiral pyrrolidines/piperidines can be synthesizedvia asymmetric hydrogenation of 18 using chiral catalysts (see Parshall,G. W. Homogeneous Catalysis, John Wiley and Sons, New York: 1980, pp.43-45; Collman, J. P., Hegedus, L. S. Principles and Applications ofOrganotransition Metal Chemistry, University Science Books, Mill Valley,Calif., 1980, pp. 341-348).

The cyanoguanidines (Z═N—CN) can be synthesized by the method of K. S.Atwal, et al. and references contained therein (J. Med. Chem. (1998) 41,217-275). The nitroethylene analog (Z═C—NO2) can be synthesized by themethod of F. Moimas, et al. (Synthesis 1985, 509-510) and referencescontained therein. The malononitrile analog (Z═C(CN)2) may besynthesized by the method of S. Sasho, et al. (J. Med. Chem. 1993, 36,572-579).

Guanidines (Z═NR^(1a)) can be synthesized by the methods outlined inScheme 3. Compound 21 where Z═S can be methylated to yield themethylisothiourea 22. Displacement of the SMe group with amines yieldssubstituted guanidines 23 (see H. King and I. M. Tonkin J. Chem. Soc.1946, 1063 and references therein). Alternatively, reaction of thiourea21 with amines in the presence of triethanolamine and “lac sulfur” whichfacilitates the removal of H₂S yields substituted guanidines 23 (K.Ramadas, Tet. Lett. 1996, 37, 5161 and references therein). Finally, theuse of carbonimidoyldichloride 24, or 25 followed by sequentialdisplacements by amines yields the corresponding substituted guanidine23 (S. Nagarajan, et al., Syn. Comm. 1992, 22, 1191-8 and referencestherein). In a similar manner, carbonimidoyldichlorides, R²—N═C(Cl)₂(not shown in Scheme 3) and R³—N═C(Cl)₂ (not shown) can also be reactedsequentially with amines to yield di- and trisubstituted guanidine 23.

A method for introducing substituents in linkage E is that of A. Chesneyet al. (Syn. Comm. 1990, 20 (20), 3167-3180) as shown in Scheme 4.Michael reaction of pyrrolidine or piperidine 1 with Michael acceptor 26yields intermediate 27 which can undergo subsequent reactions in thesame pot. For example, reduction yields alcohol 28 which can beelaborated to the amine 29 by standard procedures familiar to oneskilled in the art. Some of these include mesylation or tosylationfollowed by displacement with NaN₃ followed by reduction to yield amine29. Another route as depicted in Scheme 4 involves reaction withdiphenylphosphoryl azide followed by reduction of the azide to yieldamine 29.

The mesylate or tosylate can also be displaced by other nucleophilessuch as NH₃, BOC₂N⁻, potassium phthalimide, etc., with subsequentdeprotection where necessary to yield amines 29. Finally, 29 can beconverted to urea or thiourea 30 by procedures discussed for Scheme 1 orto the compounds of this invention by procedures previously discussed.Similarly, aldehyde 27 may be reacted with a lithium or a Grignardreagent 31 to yield alcohol adduct 32. This in turn can be converted tourea or thiourea 34 in the same way as discussed for the conversion of28 to 30.

Scheme 5 shows that intermediate 36 can be extended via a Wittigreaction (A. Chesney, et al. Syn. Comm. 1990, 20 (20), 3167-3180) toyield 37. This adduct can be reduced catalytically to yield 38 or byother procedures familiar to one skilled in the art. Alkylation yields39, followed by saponification and Curtius rearrangement (T. L. Capsonand C. D. Poulter, Tet. Lett., (1984) 25, 3515-3518) followed byreduction of the benzyl protecting group yields amine 40 which can beelaborated further as was described earlier in Scheme 1 and elsewhere inthis application to make the compounds of this invention. Dialkyllithiumcuprate, organocopper, or copper-catalyzed Grignard addition (for areview, see G. H. Posner, “An Introduction to Synthesis UsingOrganocopper Reagents”, J. Wiley, New York, 1980; Organic Reactions, 19,1 (1972)) to alpha,beta-unsaturated ester 37 yields 41 which can undergosubsequent transformations just discussed to yield amine 43 which can beelaborated further to the compounds of this invention as was describedearlier. The intermediate enolate ion obtained upon cuprate addition to37 can also be trapped by an electrophile to yield 42 (for a review, seeR. J. K. Taylor, Synthesis 1985, 364). Likewise, another 2-carbonhomologation is reported by A. Chesney et al. (ibid.) on intermediate 36which involves reacting 36 with an enolate anion to yield aldolcondensation product 42 where R¹²═OH. The OH group can undergo synthetictransformations which are familiar to one skilled in the art and whichwill be discussed in much detail later on in the application. Chiralauxilliaries can also be used to introduce stereo- andenantioselectivity in these aldol condensations, procedures which arefamiliar to one skilled in the art.

Examples of such methods are taught in D. A. Evans, et al., J. Am. Chem.Soc. 1981, 103, 2127; D. A. Evans, J. Am. Chem. Soc. 1982, 104, 1737; D.A. Evans, J. Am. Chem. Soc. 1986, 108, 2476; D. A. Evans. et al., J. Am.Chem. Soc. 1986, 108, 6757; D. A. Evans, J. Am. Chem. Soc. 1986, 108,6395; D. A. Evans, J. Am. Chem. Soc. 1985, 107, 4346; A. G. Myers, etal., J. Am. Chem. Soc. 1997, 119, 6496. One can also perform anenantioselective alkylation on esters 38 or 41 with R¹²X where X is aleaving group as described in Scheme 1, provided the ester is firstattached to a chiral auxiliary (see above references of Evans, Myers andMauricio de L. Vanderlei, J. et al., Synth. Commum. 1998, 28, 3047).

One can also react alpha,beta-unsaturated ester 37 (Scheme 6) withCorey's dimethyloxosulfonium methylide (E. J. Corey and M. Chaykovsky,J. Am. Chem. Soc. 1965, 87, 1345) to form a cyclopropane which canundergo eventual Curtius rearrangement and subsequent elaboration to thecompounds of this invention wherein the carbon containing R⁹R¹⁰ is tiedup in a cyclopropane ring with the carbon containing R¹¹R¹². Inaddition, compound 48 can also undergo the analogous reactions justdescribed to form cyclopropylamine 50 which can be further elaboratedinto the compounds of this invention as described previously. Compound48 may be synthesized by an alkylation reaction ofpyrrolidine/piperidine 1 with bromide 47 in an inert solvent employingthe conditions as described for the alkylation of 2 onto 1 in Scheme 1.

Another way to synthesize the compounds in the scope of this applicationis shown in Scheme 7. Michael reaction of amine 1 with an acrylonitrile51 (as described by I. Roufos in J. Med. Chem. 1996, 39, 1514-1520)followed by Raney-Nickel hydrogenation yields amine 53 which can beelaborated to the compounds of this invention as previously described.

In Schemes 4, 5, and 6, we see that there is no gem-substitution on thealpha-carbon to the electron-withdrawing group of what used to be theMichael acceptor. In other words, in Scheme 4, there is no R¹⁰ gem toR⁹; in Scheme 5, there is no R¹⁰ gem to one of the R⁹s and in Scheme 7there is no R¹⁰ gem to R⁹. Gem-substitution can be introduced byreacting pyrrolidine or piperidine 1 with the epoxide of Michaelacceptors 26, 35, and 51 to yield the corresponding alcohols (for aminesreacting with epoxides of Michael acceptors, see Charvillon, F. B.;Amouroux, R.; Tet. Lett. 1996, 37, 5103-5106; Chong, J. M.; Sharpless,K. B.; J Org Chem 1985, 50, 1560). These alcohols eventually can befurther elaborated into R¹⁰ by one skilled in the art, as, for example,by tosylation of the alcohol and cuprate displacement (Hanessian, S.;Thavonekham, B.; DeHoff, B.; J Org. Chem. 1989, 54, 5831), etc., and byother displacement reactions which will be discussed in great detaillater on in this application.

Further use of epoxides to synthesize compounds of this invention areshown in Scheme 8. Reaction of pyrrole or piperidine 1 with epoxide 54yields protected amino-alcohol 55. This reaction works exceptionaly wellwhen R⁷ and R⁸ are H but is not limited thereto. The reaction isperformed in an inert solvent at room temperature to the refluxtemperature of the solvent. Protecting groups on the nitrogen atom of 54include BOC and CBZ but are not limited thereto. The hydroxyl group canbe optionally protected by a variety of protecting groups familiar toone skilled in the art.

Deprotection of the nitrogen by methods familiar to one skilled in theart yields 56 which can be elaborated to the compounds of this inventionby the procedures previously discussed. If R⁹═H, then oxidation, forexample, by using PCC (Corey E. J. and Suggs, J. W., Tet. Lett. 1975,31, 2647-2650) or with the Dess-Martin periodinane (Dess, D. B. andMartin, J. C., J. Org. Chem. 1983, 48, 4155-4156) yields ketone 57 whichmay undergo nucleophilic 1,2-addition with organometallic reagents suchas alkyl- or aryllithiums, Grignards, or zinc reagents, with or withoutCeCl₃ (T. Imamoto, et al., Tet. Lett. 1985, 26, 4763-4766; T. Imamoto,et al., Tet. Lett. 1984, 25, 4233-4236) in aprotic solvents such asether, dioxane, or THF to yield alcohol 58. The hydroxyl group can beoptionally protected by a variety of protecting groups familiar to oneskilled in the art. Deprotection of the nitrogen yields 56 which can befinally elaborated to the compounds of this invention as previouslydiscussed. Epoxides disclosed by structure 54 may be synthesizedenantio-selectively from amino acid starting materials by the methods ofDellaria, et al. J Med Chem 1987, 30 (11), 2137, and Luly, et al. J OrgChem 1987, 52 (8), 1487.

The carbonyl group of ketone 57 in Scheme 8 may undergo Wittig reactionsfollowed by reduction of the double bond to yield alkyl, arylalkyl,heterocyclic-alkyl, cycloalkyl, cycloalkylalkyl, etc. substitution atthat position, reactions that are familiar to one skilled in the art.Wittig reagents can also contain functional groups which after reductionof the double bond yield the following functionality: esters (Buddrus,J. Angew Chem., 1968, 80), nitrites (Cativiela, C. et al., Tetrahedron1996, 52 (16), 5881-5888.), ketone (Stork, G. et al., J Am Chem Soc1996, 118 (43), 10660-10661), aldehyde and methoxymethyl (Bertram, G. etal., Tetrahedron Lett 1996, 37 (44), 7955-7958.), gamma-butyrolactoneVidari, G. et al., Tetrahedron: Asymmetry 1996, 7 (10), 3009-3020.),carboxylic acids (Svoboda, J. et al., Collect Czech Chem Commun 1996, 61(10), 1509-1519), ethers (Hamada, Y. et al., Tetrahedron Lett 1984, 25(47), 5413), alcohols (after hydrogenation and deprotection—Schonauer,K.; Zbiral, E.; Tetrahedron Lett 1983, 24 (6), 573), amines (Marxer, A.;Leutert, T. Helv Chim Acta, 1978, 61) etc., all of which may furtherundergo transformations familiar to one skilled in the art to form awide variety of functionality at this position.

Scheme 9 summarizes the displacement chemistry and subsequentelaborations that can be used to synthesize the R⁹ groups. In Scheme 9we see that alcohol 55 or 58 may be tosylated, mesylated, triflated, orconverted to a halogen by methods familiar to one skilled in the art toproduce compound 59. (Note that all of the following reactions in thisparagraph can be also performed on the compounds, henceforth calledcarbon homologs of 55 or 58 where OH can be (CH₂)_(r)OH and it is alsounderstood that these carbon homologs may have substituents on themethylene groups as well). For example, a hydroxyl group may beconverted to a bromide by CBr₄ and Ph₃P (Takano, S. Heterocycles 1991,32, 1587). For other methods of converting an alcohol to a bromide or toa chloride or to an iodide see R. C. Larock, Comprehensive OrganicTransformations, VCH Publishers, New York, 1989, pp. 354-360. Compound59 in turn may be displaced by a wide variety of nucleophiles as shownin Scheme 9 including but not limited to azide, cyano, malonate,cuprates, potassium thioacetate, thiols, amines, etc., all nucleophilicdisplacement reactions being familiar to one skilled in the art.Displacement by nitrile yields a one-carbon homologation product.Nitrile 60 can be reduced with DIBAL to yield aldehyde 61. This aldehydecan undergo reduction to alcohol 62 with, for example, NaBH₄ which inturn can undergo all of the S_(N)2 displacement reactions mentioned foralcohol 55 or 58. Alcohol 62 is a one carbon homolog of alcohol 55 or58. Thus one can envision taking alcohol 62, converting it to a leavinggroup X as discussed above for compound 55 or 58, and reacting it withNaCN or KCN to form a nitrile, subsequent DIBAL reduction to thealdehyde and subsequent NaBH₄ reduction to the alcohol resulting in atwo carbon homologation product. This alcohol can undergo activationfollowed by the same S_(N)2 displacement reactions discussed previously,ad infinitum, to result in 3, 4, 5 . . . etc. carbon homologationproducts. Aldehyde 61 can also be reacted with a lithium or Grignardreagent to form an alcohol 61a which can also undergo the abovedisplacement reactions. Oxidation by methods familiar to one skilled inthe art yields ketone 61b. Displacement by malonate yields malonic ester63 which can be saponified and decarboxylated to yield carboxylic acid64, a two carbon homologation product. Conversion to ester 65 (A.Hassner and V. Alexanian, Tet. Lett, 1978, 46, 4475-8) and reductionwith LAH yields alcohol 68 which can undergo all of the displacementreactions discussed for alcohol 55 or 58. Alcohols may be converted tothe corresponding fluoride 70 by DAST (diethylaminosulfur trifluoride)(Middleton, W. J.; Bingham, E. M.; Org. Synth. 1988, VI, pg. 835).Sulfides 71 can be converted to the corresponding sulfoxides 72 (p=1) bysodium metaperiodate oxidation (N. J. Leonard, C. R. Johnson J. Org.Chem. 1962, 27, 282-4) and to sulfones 72 (p=2) by Oxone® (A. Castro, T.A. Spencer J. Org. Chem. 1992, 57, 3496-9). Sulfones 72 can be convertedto the corresponding sulfonamides 73 by the method of H. -C. Huang, E.et al., Tet. Lett. (1994) 35, 7201-7204 which involves first, treatmentwith base followed by reaction with a trialkylborane yielding a sulfinicacid salt which can be reacted with hydroxylamine-O-sulfonic acid toyield a sulfonamide. Another route to sulfonamides involves reaction ofamines with a sulfonyl chloride (G. Hilgetag and A. Martini, PreparativeOrganic Chemistry, New York: John Wiley and Sons, 1972, p. 679). Thissulfonyl chloride (not shown in Scheme 9) can be obtained from thecorresponding sulfide (71 where R^(9d)=H in Scheme 9, the hydrolysisproduct after thioacetate displacement), disulfide, or isothiouroniumsalt by simply reacting with chlorine in water. The isothiouronium saltmay be synthesized from the corresponding halide, mesylate or tosylate59 via reaction with thiourea (for a discussion on the synthesis ofsulfonyl chlorides see G. Hilgetag and A. Martini, ibid., p. 670).Carboxylic acid 64 can be converted to amides 66 by standard couplingprocedures or via an acid chloride by Schotten-Baumann chemistry or to aWeinreb amide (66: R^(9a)=OMe, R^(9a)′=Me in Scheme 9) (S. Nahm and S.M. Weinreb, Tet. Lett., 1981, 22, 3815-3818) which can undergo reductionto an aldehyde 67 (R^(9b)=H in Scheme 9) with LAH (S. Nahm and S. M.Weinreb, ibid.) or reactions with Grignard reagents to form ketones 67(S. Nahm and S. M. Weinreb, ibid.). The aldehyde 67 obtained from theWeinreb amide reduction can be reduced to the alcohol with NaBH₄. Thealdehyde or ketone 67 (or 61 or 61b for that matter) can undergo Wittigreactions as discussed previously followed by optional catalytichydrogenation of the olefin. This Wittig sequence is one method forsynthesizing the carbocyclic and heterocyclic substituted systems at R⁹employing the appropriate carbocyclic or heterocyclic Wittig (orHorner-Emmons) reagents. Of course, the Wittig reaction may also be usedto synthesize alkenes at R⁹ and other functionality as well. Ester 65can also form amides 66 by the method of Weinreb (A. Basha, M. Lipton,and S. M. Weinreb, Tet. Lett. 1977, 48, 4171-74) (J. I. Levin, E. Turos,S. M. Weinreb, Syn. Comm. 1982, 12, 989-993). Alcohol 68 can beconverted to ether 69 by procedures familiar to one skilled in the art,for example, NaH, followed by an alkyliodide or by Mitsunobu chemistry(Mitsunobu, O. Synthesis, 1981, 1-28). Alcohol 55 or 58, 62, or 68, canbe acylated by procedures familiar to one skilled in the art, forexample, by Schotten-Baumann conditions with an acid chloride or by ananhydride with a base such as pyridine to yield 78. Halide, mesylate,tosylate or triflate 59 can undergo displacement with azide followed byreduction to yield amine 74 a procedure familiar to one skilled in theart. This amine can undergo optional reductive amination and acylationto yield 75 or reaction with ethyl formate (usually refluxing ethylformate) to yield formamide 75. Amine 74 can again undergo optionalreductive amination followed by reaction with a sulfonyl chloride toyield 76, for example under Schotten-Baumann conditions as discussedpreviously. This same sequence may be employed for amine 60a, thereduction product of nitrile 60. Tosylate 59 can undergo displacementwith cuprates to yield 77 (Hanessian, S.; Thavonekham, B.; DeHoff, B.; JOrg. Chem. 1989, 54, 5831). Aldehyde 61 or its homologous extensions canbe reacted with a carbon anion of an aryl (phenyl, naphthalene, etc.) orheterocyclic group to yield an aryl alcohol or a heterocyclic alcohol.If necessary, CeCl₃ may be added (T. Imamoto, et al., Tet. Lett. 1985,26, 4763-4766; T. Imamoto, et al., Tet. Lett. 1984, 25, 4233-4236). Thisalcohol may be reduced with Et₃SiH and TFA (J. Org. Chem. 1969, 34, 4;J. Org. Chem. 1987, 52, 2226) (see discussion of aryl and heterocyclicanions for Schemes 20-22). These aryl and heterocyclic anions may alsobe alkylated by 59 (or its carbon homolog) to yield compounds where R⁹contains an aryl or heterocyclic group. Compound 59 or its carbonhomologs may be alkylated by an alkyne anion to produce alkynes at R⁹(see R. C. Larock, Comprehensive Organic Transformations, New York,1989, VCH Publishers, p 297). In addition, carboxaldehyde 61 or itscarbon homologs can undergo 1,2-addition by an alkyne anion (Johnson, A.W. The Chemistry of Acetylenic Compounds. V. 1. “Acetylenic Alcohols,”Edward Arnold and Co., London (1946)). Nitro groups can be introduced bydisplacing bromide 59 (or its carbon homologs) with sodium nitrite inDMF (J. K. Stille and E. D. Vessel J. Org. Chem. 1960, 25, 478-490) orby the action of silver nitrite on iodide 59 or its carbon homologs(Org. Syntheses 34, 37-39).

If an anion is made of the pyrrolidine/piperidine 1 with LDA or n-BuLi,etc., then that anion in a suitable nonhydroxylic solvent such as THF,ether, dioxane, etc., can react in a Michael-type fashion (1,4-addition)with an alpha,beta-unsaturated ester to yield an intermediate enolatewhich can be quenched with an electrophile (R⁹X) (where X is asdescribed in Scheme 1) (Uyehara, T.; Asao, N.; Yamamoto, Y.; J Chem Soc,Chem Commun 1987, 1410) as shown in Scheme 10.

It is to be understood that R⁹ is either in its final form or in asuitable protected precursor form. This electrophile can be acarbon-based electrophile, some examples being formaldehyde to introducea CH₂OH group, an aldehyde or a ketone which also introduces aone-carbon homologated alcohol, ethylene oxide (or other epoxides) whichintroduces a —CH₂CH₂OH group (a two-carbon homologated alcohol), analkyl halide, etc., all of which can be later elaborated into R⁹. It canalso be an oxygen-based electrophile such as MCPBA, Davis' reagent(Davis, F. A.; Haque, M. S.; J Org Chem 1986, 51 (21),4083; Davis, F.A.; Vishwaskarma, L. C.; Billmers, J. M.; Finn, J.; J Org Chem 1984, 49,3241) or MoO₅ (Martin, T. et al., J Org Chem 1996, 61 (18), 6450-6453)which introduces an OH group. These OH groups can undergo thedisplacement reactions discussed previously in Scheme 9 or protected bysuitable protecting groups and deprotected at a later stage when thedisplacement reactions decribed in Scheme 9 can be performed. Inaddition, these OH groups can also undergo displacement reactions withheterocycles as described for Schemes 19-22 to introduce N- orC-substituted heterocycles at this position. Ester 80 can be convertedinto its Weinreb amide 82 (S. Nahm and S. M. Weinreb, Tet. Lett., 1981,22, 3815-3818) or Weinreb amide 82 can be synthesized via Michael-typeaddition of 1 to alpha,beta-unsaturated Weinreb amide 83. Subsequentreaction with a Grignard reagent forms ketone 85. This ketone can alsobe synthesized in one step directly from 1 and alpha,beta-unsaturatedketone 84 using the same procedure. This ketone may be reduced with LAH,NaBH₄ or other reducing agents to form alcohol 86. Or else, ketone 85can be reacted with an organolithium or Grignard reagents to formtertiary alcohol 87. Or else, ester 80 can be directly reduced withLiBH₄ or LAH to yield primary alcohol 88.

Alcohols 86, 87, and 88 can all be tosylated, mesylated, triflated, orconverted to a halogen by methods discussed previously and displacedwith an amine nucleophile such as azide, diphenylphosphoryl azide (withor without DEAD and Ph₃P), phthalimide, etc. as discussed previously(and which are familiar to one skilled in the art) and after reduction(azide) or deprotection with hydrazine (phthalimide), for example, yieldthe corresponding amines. These can then be elaborated into thecompounds of this invention as discussed previously. Ketone 85 can alsobe converted into imine 89 which can be reacted with a Grignard reagentor lithium reagent, etc., to form a protected amine 90 which can bedeprotected and elaborated into the compounds of this invention asdiscussed previously. Some protecting groups include benzyl andsubstituted benzyl which can be removed by hydrogenation, andcyanoethyl, which can be removed with aqueous base, etc. It is to beunderstood that R⁷⁻¹² in Scheme 10 can be in their final form or inprecursor form which can be elaborated into final form by proceduresfamiliar to one skilled in the art.

Magnesium amides of amines have been used to add in a Michael-typemanner to alpha,beta-unsaturated esters where the substituents at thebeta position of the unsaturated ester are-tied together to form acyclopentane ring (for example, compound 79 where R⁷ and R⁸ are takentogether to be —(CH₂)₄—) (Kobayashi, K. et al., Bull Chem Soc Jpn, 1997,70 (7), 1697-1699). Thus reaction of pyrrolidine or piperidine 1 withcycloalkylidine esters 79 as in Scheme 10 yields esters 80 where R⁷ andR⁸ are taken together to form a cycloalkyl ring. Subsequent elaborationyields compounds of this invention where R⁷ and R⁸ are taken together toform a cycloalkyl ring.

Compounds of structure 95a may also be synthesized from epoxyalcoholswhich are shown in Scheme 11. Allylic alcohol 91 can be epoxidizedeither stereoselectively using VO(acac)₂ catalyst (for a review, seeEvans: Chem. Rev. 1993, 93, 1307) or enantioselectively (Sharpless: J.Am. Chem. Soc. 1987, 109, 5765) to epoxyalcohol 92. S_(N)2 displacementof the alcohol using zinc azide and triphenylphosphine (Yoshida, A. J.Org. Chem. 57, 1992, 1321-1322) or diphenylphosphoryl azide, DEAD, andtriphenylphosphine (Saito, A. et al., Tet. Lett. 1997, 38 (22),3955-3958) yields azidoalcohol 93. Hydrogenation over a Pd catalystyields aminoalcohol 94. This can be protected in situ or in a subsequentstep with BOC₂O to put on a BOC protecting group, or with CBZ-Cl andbase to put on a CBZ-group or other protecting groups. Alternatively,the amino group can be reacted with an isocyanate, an isothiocyanate, acarbamoyl chloride, or any reagent depicted in Scheme 1 to form 95 whichcan be alkylated with 1 to form the compounds of this invention.

Sometimes amine 1 might have to be activated with Lewis acids in orderto open the epoxide ring (Fujiwara, M.; Imada, M.; Baba, A.; Matsuda,H.;Tetrahedron Lett 1989, 30, 739; Caron, M.; Sharpless, K. B.; J OrgChem 1985, 50, 1557) or 1 has to be deprotonated and used as a metalamide, for example the lithium amide (Gorzynski-Smith, J.; Synthesis1984 (8), 629) or MgBr amide (Carre, M. C.; Houmounou, J. P.; Caubere,P.; Tetrahedron Lett 1985, 26, 3107) or aluminum amide (Overman, L. E.;Flippin, L. A.; Tetrahedron Lett 1981, 22, 195).

The quaternary salts (where R⁴ is present as a substituent) ofpyrrolidines and piperidines can be synthesized by simply reacting theamine with an alkylating agent, such as methyl iodide, methyl bromide,ethyl iodide, ethyl bromide, ethyl or methyl bromoacetate,bromoacetonitrile, allyl iodide, allylbromide, benzyl bromide, etc. in asuitable solvent such as THF, DMF, DMSO, etc. at room temperature to thereflux temperature of the solvent. Spiroquaternary salts can besynthesized in a similar manner, the only difference being that thealkylating agent is located intramolecularly as shown in Scheme 12. Itis understood by one skilled in the art that functional groups might notbe in their final form to permit cyclization to the quaternary ammoniumsalt and might have to be in precursor form or in protected form to beelaborated to their final form at a later stage. For example, theNR¹(C═Z)NR²R³ group on the rightmost phenyl ring of compound 104 mightexist as a nitro group precursor for ease of manipulation duringquaternary salt formation. Subsequent reduction and NR¹(C═Z)NR²R³ groupformation yields product 105. The leaving groups represented by X inScheme 12 may equal those represented in Scheme 1, but are not limitedthereto. N-oxides of pyrrolidines and piperidines can be made by theprocedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514). This simplyentails reacting the pyrrolidine or piperidine with MCPBA, for example,in an inert solvent such as methylene chloride.

Multisubstituted pyrrolidines and piperidines may be synthesized by themethods outlined in Scheme 13. Monoalkylation of 106 via an enolateusing LDA or potassium hexamethyldisilazane, or converting 106 first toan enamine, or by using other bases, all of which can be done in THF,ether, dioxane, benzene, or an appropriate non-hydroxylic solvent at−78° C. to room temperature with an alkylating agent such as methyliodide, benzyl bromide, etc. where X is as defined in Scheme 1, yieldsproduct 107. This product can subsequently undergo alkylation againunder thermodynamic or kinetic conditions and afterwards, if need be,can undergo two more alkylations to produce tri- and tetrasubstitutedanalogs of 107. The thermodynamic or kinetic conditions yieldregioselectively alkylated products (for a discussion on thermodynamicvs. kinetic alkylations see H. House Modern Synthetic Reactions, W. A.Benjamin, Inc. (Menlo Park, Calif.: 1972) chapter 9).

Subsequent Wittig olefination yields compound 108. Hydrogenation(asymmetric hydrogenation is an option here: Parshall, G. W. HomogeneousCatalysis, John Wiley and Sons, New York: 1980, pp. 43-45; Collman, J.P., Hegedus, L. S. Principles and Applications of Organotransition MetalChemistry, University Science Books, Mill Valley, Calif., 1980, pp.341-348) yields pyrrolidine or piperidine 109 which can be resolved intoits relative and/or absolute isomers at this stage or later on in thesynthesis either by crystallization, chromatographic techniques, orother methods familiar to one skilled in the art. The amine 109 an thenbe elaborated into the compounds of this invention by methods discussedpreviously (Scheme 1). The carbonyl-containing intermediate 107 inScheme 13 can also be reduced to the methylene analog via aWolff-Kishner reduction and modifications thereof, or by other methodsfamiliar to one skilled in the art. The carbonyl group can also bereduced to an OH group, which can undergo all of the reactions describedin Scheme 9 to synthesize the R6 groups. This piperidine or pyrrolidinecan be deprotected and elaborated to the compounds of this invention bymethods discussed earlier. Thus, mono-, di-, tri-, or tetraalkylatedcarbonyl-containing pyrrolidines or piperidines can be synthesized,which in turn can be reduced to the corresponding —CH2— analogsemploying the Wolff-Kishner reduction or other methods.

Another method for synthesizing gem-substituted pyrrolidines andpiperidines is shown in Scheme 14. It is understood by one skilled inthe art that some of the steps in this scheme can be rearranged. It isalso understood that gem-disubstitution is only shown at only oneposition on the piperidine ring and that similar transformations may beperformed on other carbon atoms as well, both for piperidine andpyrrolidine. Thus, 3-carboethoxypiperidine 110 may be BOC-protected andalkylated employing a base such as LDA, KHMDS, LHDMS, etc., in THF,ether, dioxane, etc. at −78° C. to room temperature, and an alkylatingagent R⁶X where X is a halide (halide=Cl, Br, I), mesylate, tosylate ortriflate, to yield 112. Reduction using DIBAL, for example, and ifnecessary followed by oxidation such as a Swern oxidation (S. L. Huang,K. Omura, D. Swern J. Org. Chem. 1976, 41, 3329-32) yields aldehyde 113.Wittig olefination (114) followed by deprotection yields 115 which maybe elaborated as described previously into the compounds of thisinvention. Reduction of the Wittig adduct 114 yields 116 which may bedeprotected to yield 117 which may be in turn elaborated as describedpreviously into the compounds of this invention. Reaction of aldehyde113 with an alkyllithium or Grignard reagent yields alcohol 118 whichmay be reduced catalytically or with Et₃SiH/TFA (J. Org. Chem. 1969, 34,4; J. Org. Chem. 1987, 52, 2226) if R^(5*) (R^(5*)=R⁵ or a precursorthereof) is aromatic to yield 119. If R⁵* is not aromatic, then the OHmay be reduced by the method of Barton (Barton, D. H. R.; Jaszberenyi,J. C. Tet. Lett. 1989, 30, 2619 and other references therein). Oncetosylated, the alcohol can also be displaced with dialkyllithiumcuprates (not shown) (Hanessian, S.; Thavonekham, B.; DeHoff, B.; J Org.Chem. 1989, 54, 5831). Deprotection if necessary yields 120 which may beelaborated as described previously into the compounds of this invention.

A method for the alkylation of alkyl groups, arylalkyl groups, allylicgroups, propargylic groups, etc., and a variety of other electrophilesonto the pyrrolidinyl and/or piperidinyl alpha-carbons (alpha to thering nitrogen atom) is represented by the work of Peter Beak, et al. asshown in Scheme 15. It is understood by one skilled in the art that theR⁵ and R¹³ groups are either in their precursor, protected, or finalform. Only one R⁵ group is shown to be substituted onpiperidine/pyrrolidine 121. However it is understood by one skilled inthe art that additional functionality may be present on the ring ineither precursor, protected, or final form. Thus lithiation with analkyllithium reagent such as n-BuLi or s-BuLi as shown, followed byquenching with an electrophilic species such as R⁵X or R¹³X where X isas defined in Scheme 1 and R⁵ and R¹³ are in their precursor, protected,or final form, yields monoalkylated piperidine/pyrrolidine 122. Thisalkylation may occur either stereoselectively (P. Beak and W. K. Lee J.Org. Chem. 1990, 55, 2578-2580) or enantioselectively if sparteine isincluded as a source of chirality (P. Beak, et al., J. Am. Chem. Soc.1994, 116, 3231-3239). The alkylation process may be repeated up tothree more times as shown in Scheme 15 to result in di-, tri-, andtetrasubstitution at the alpha-positions.

Compounds where R⁹ and R¹⁰ form a cyclic 3, 4, 5, 6, or 7-membered ringcan be synthesized by the methods disclosed in Scheme 16. These samemethods may also be used to synthesize gem-disubstituted compounds inwhich R⁹ can be different from R¹⁰ by step-wise alkylation of themalonate derivative. Of course, this scheme may be used to synthesizecompounds where R¹⁰=H also. For example, a cyclohexyl-fused malonate maybe synthesized by Michael addition and alkylation of I(CH2)₄CH═CCO₂Mewith dimethyl malonate employing NaH/DMF (Desmaele, D.; Louvet, J. -M.;Tet Lett 1994, 35 (16), 2549-2552) or by a double Michael addition(Reddy, D. B., et al., Org. Prep. Proced. Int. 24 (1992) 1, 21-26)(Downes, A. M.; Gill, N. S.; Lions, F.; J Am Chem or by an alkylationfollowed by a second intromolecular alkylation employing an iodoaldehyde(Suami, T.; Tadano, K.; Kameda, Y.; Iimura, Y.; Chem Lett 1984, 1919),or by an alkylation followed by a second intramolecular alkylationemploying an alkyl dihalide (Kohnz, H.; Dull, B.; Mullen, K.; Angew Chem1989, 101 (10), 1375), etc.

Subsequent monosaponification (Pallai, P. V., Richman, S., Struthers, R.S., Goodman, M. Int. J. Peptide Protein Res. 1983, 21, 84-92; M. GoodmanInt. J. Peptide Protein Res. 19831, 17, 72-88), standard coupling withpyrrolidine/piperidine 1 yields 128. Reduction with borane yields 129followed by reduction with LAH yields 130 which can be then converted toamine 131 and then to the compounds of this invention by procedures asdiscussed previously. Ester 129 can also be converted to a Weinreb amideand elaborated to the compounds of this invention as described in Scheme10 for ester 80 which would introduce substituents R¹¹ and R¹².

Scheme 17 describes another method for the synthesis of compounds whereR⁹ and R¹⁰ are taken together to form cycloalkyl groups. Aminoalcohols132 are found in the literature (CAS Registry Nos. for n=0, 1, 2, 3,respectively: 45434-02-4, 2041-56-7, 2239-31-8, 2041-57-8). They caneasily be protected, as with a BOC group (or CBZ, or any othercompatible protecting group) by known procedures familiar to one skilledin the art to yield alcohols 133. The alcohols can then be activatedeither by conversion to a halide or to a mesylate, tosylate or triflateby methods familiar to one skilled in the art and as discussedpreviously, and then alkylated with pyrrolidine/piperidine 1 by theconditions described in Scheme 1 to yield 135. Subsequent deprotectionyields amine 136 which can be elaborated to the compounds of thisinvention as described previously. Of course, alcohol 133 can beoxidized to the aldehyde and then reacted with R^(7 or 8)MgBr orR^(7 or 8)Li with or without CeCl₃ to yield the corresponding alcohol133 where instead of —CH₂OH, we would have —CHR^(7 or 8)OH. Thisoxidation-1,2-addition sequence may be repeated to yield a tertiaryalcohol. The alcohol may then be tosylated, mesylated, triflated, orconverted to Cl, Br, or I by procedures familiar to one skilled in theart to yield 134 and then displaced with pyrrolidine/piperidine 1 toyield 135. Subsequent deprotection yields 136 which may undergoelaboration to the compounds of this invention as discussed previously.

A method to introduce cycloalkyl groups at R¹¹R¹² is shown in Scheme 18.Protection of the nitrogen of compounds 137 which are commerciallyavailable yields 138 (the protecting group may be BOC, CBZ, or any othercompatible protecting group) by procedures familiar to one skilled inthe art. Esterification by any one of a number procedures familiar toone skilled in the art (for example A. Hassner and V. Alexanian, Tet.Lett, 1978, 46, 4475-8) followed by reduction with DIBAL (oralternatively reduction to the alcohol with, for example, LiBH₄,followed by Swern oxidation (op. cit.)) yields aldehyde 139. One carbonhomologation via the Wittig reaction followed by hydrolysis of the vinylether yields aldehyde 141. Reductive amination (Abdel-Magid, A. F., etal. Tet. Lett. 1990, 31, (39) 5595-5598) yields 142 followed bydeprotection yields amine 143 which can be elaborated to the compoundsof this invention by the methods previously discussed. Of course,aldehyde 139 can be reacted with R^(9 or 10)MgBr or R^(9 or 10)Li withor without CeCl₃ to yield an alcohol which can be oxidized to a ketone.Wittig one-carbon homologation on this ketone as described abovefollowed by hydrolysis yields 141 where the —CH₂CHO is substituted withone R^(9 or 10)group (—CHR^(9 or 10)CHO).

Aldehyde 141 (—CH₂CHO) or its monosubstituted analog synthesized above(—CHR^(9 or 10)CHO) can undergo alkylation with R^(9 or 10)X where X isas defined in Scheme 1 to yield compound 141 containing one or both ofthe R⁹ and R¹⁰ substituents alpha to the aldehyde group. Alkylation canbe performed using LDA or lithium bistrimethylsilyl amide amongst otherbases in an inert solvent such as ether, THF, etc., at −78° C. to roomtemperature. Aldehyde 141 (—CH₂CHO) or its substituted analogssynthesized above (i.e., —CHR⁹R¹⁰CHO) can undergo reductive aminationwith 1 and subsequent elaboration to the compounds of this invention.Aldehyde 141 (—CH₂CHO)or its substituted analogs synthesized above(i.e., —CHR⁹R¹⁰CHO) can also undergo 1,2-addition with R^(7 or 8)MgBr orR^(7 or 8)Li to yield the corresponding alcohol —CH₂CHR^(7 or 8)OH or—CHR⁹R¹⁰CHR^(7 or 8)OH. The alcohol may then be tosylated, mesylated,triflated, or converted to Cl, Br, or I by procedures familiar to oneskilled in the art and displaced with pyrrolidine/piperidine 1 to yield,after subsequent deprotection and elaboration, the compounds of thisinvention. Or else alcohol —CH₂CHR^(7 or 8)OH or —CR⁹R¹⁰CHR^(7 or 8)OHcan be oxidized (i.e., Swern, op. cit.) to the ketone and reductivelyaminated with 1 and subsequently elaborated to the compounds of thisinvention. Or else alcohol —CH₂CHR^(7 or 8)OH or —CR⁹R¹⁰CHR^(7 or 8)OHcan be oxidized (i.e., Swern, op. cit.) to the ketone and reacted oncemore with R^(7 or 8)MgBr or R^(7 or 8)Li to yield the correspondingalcohol —CH₂CR⁷R⁸OH or —CR⁹R¹⁰CR⁷R⁸OH. If the ketone enolizes easily,CeCl₃ may be used together with the Grignard or lithium reagent. Thealcohol can again be tosylated, mesylated, triflated, or converted toCl, Br, or I by procedures familiar to one skilled in the art anddisplaced with pyrrolidine/piperidine 1 to yield, after subsequentdeprotection and elaboration, the compounds of this invention. Thus eachone of the R⁷, R⁸, R⁹, and R¹⁰ groups may be introduced into compounds141, 142 and 143 and and, of course, in the compounds of this invention,by the methods discussed above.

A method for the synthesis of N-substituted heterocycles at R⁵ is shownin Scheme 19. The heterocycle can be deprotonated with NaH or by otherbases familiar to one skilled in the art, in a solvent such as DMF, THF,or another appropriate non-hydroxylic solvent and reacted withpiperidine or pyrrolidine 143 at room temperature to the refluxtemperature of the solvent. Deprotection and elaboration as describedbefore yields compounds where R⁵ contains an N-substituted heterocycle.If the nitrogen atom of the heterocycle is sufficiently nucleophilic,then an acid scavenger, such as K₂CO₃, KHCO₃, Na₂CO₃, NaHCO₃, amongstothers, can be used in place of NaH, employing THF, DMF, or methyl ethylketone as solvents. In this case hydroxylic solvents may be used aswell, such as methanol, ethanol, etc. from room temperature to thereflux temperature of the solvent. Compound 143 as well as its otherpositional isomers are available, for example, from commerciallyavailable 4-hydroxymethylpiperidine, 2-, 3-, and4-carboethoxypiperidine, L- or D-proline ethyl ester, or from methyl1-benzyl-5-oxo-3-pyrrolidinecarboxylate by methods familiar to oneskilled in the art and as discussed previously in this application.

A method for the synthesis of C-substituted heterocycles at R⁵ is shownin Scheme 20. Many heterocycles such as the ones shown in Scheme 20, butnot limited thereto, can be metallated with strong bases such as LDA,n-BuLi, sec-BuLi, t-BuLi, etc. to yield the corresponding anionicspecies. These anions may also be generated via halogen-metal exchangeemploying n-BuLi, or other alkyllithium reagents. These reactions may beperformed in THF, ether, dioxane, DME, benzene, etc. at −78° C. to roomtemperature.

For reviews of these metallations and halogen-metal exchange reactionssee Organometallics in Organic Synthesis, FMC Corp., Lithium Division,1993, pp. 17-39; Lithium Link, FMC Corp., Spring 1993, pp. 2-17;n-Butyllithium in Organic Synthesis, Lithium Corp. of America, 1982, pp.8-16; G. Heinisch, T. Langer, P. Lukavsky, J. Het. Chem. 1997, 34,17-19. The anions can then be quenched with electrophile 143 or itspositional isomers to yield the corresponding C-alkylated heterocyclicpyrrolidine or piperidine 145.

Another method for the synthesis of C-substitutedheterocyclic-methylpyrrolidines or piperidines is shown in Scheme 21.The protected aldehyde 146 is reacted with the anion of the heterocycle(its generation as described previously) at −78° C. to room temperaturewith or without CeCl₃ in an inert solvent such as THF, ether, dioxane,DME, benzene, etc. to yield carbinol 147. Catalytic hydrogenation of thealcohol yields the corresponding methylene compound 145. Other reductionmethods include Et₃SiH/TFA (J. Org. Chem. 1969, 34, 4; J. Org. Chem.1987, 52, 2226) amongst others familiar to one skilled in the art. It isunderstood by one skilled in the art that the aldehyde group can belocated in other positions instead of, for example, the 4-position ofpiperidine in compound 146 as depicted in Scheme 21. It is to beunderstood that other heterocycles may also be used besides the onesshown in Scheme 20 and 21.

The anions of the methyl-substituted heterocycles may also be reactedwith a BOC-protected piperidone or pyrrolidone (148) to yield alcohols149 as shown in Scheme 22 (see above reviews on metallations forreferences). These alcohols may be reduced using PtO₂ and TFA (P. E.Peterson and C. Casey, J. Org. Chem. 1964, 29, 2325-9) to yieldpiperidines and pyrrolidines 150. These can subsequently be taken on tothe compounds of this invention as described previously. It isunderstood by one skilled in the art that the carbonyl group can belocated in other positions instead of, for example, the 4-position ofpiperidine in compound 148 as depicted in Scheme 22. It is to beunderstood that other heterocycles may also be used besides the onesshown in Scheme 22.

One may also react aryl (phenyl, naphthyl, etc.) anions, generatedeither by halogen-metal exchange or by ortho-directed metallation(Snieckus, V. Chem. Rev. 1990, 90, 879-933) using n- or s- or t-BuLi ina non-hydroxylic solvent such as THF, ether, etc., with or without TMEDAand allow them to react with compounds 143, 146. and 148 with subsequentelaboration to yield the compounds of this invention by the methodsdepicted in Schemes 19-22.

Another method for the preparation of C-substituted heterocycles isshown in Scheme 23. Protected piperidone 148 undergoes a Wittig reactionwith heterocyclic phosphorous ylides to yield 151. Hydrogenation over anoble metal catalyst such as Pd in an alcoholic solvent or with anoptically active transition metal catalyst (see asymmetric hydrogenationreferences of Parshall and Coleman, op. cit.) yields 152 which can befurther elaborated into the compounds of this invention by theprocedures described previously. It will be appreciated by one skilledin the art that the carbonyl group can be located in other positionsinstead of, for example, the 4-position of piperidine in compound 148 asdepicted in Scheme 23. It is to be understood that other heterocyclesmay also be used besides the ones shown in Scheme 23.

Syntheses of amines 9, 10, and the amines which are precursors toisocyanates or isothiocyanates 5 will now be discussed. For example,3-nitrobenzeneboronic acid (153: Scheme 24) is commerically availableand can undergo Suzuki couplings (Suzuki, A. Pure Appl. Chem. 1991, 63,419) with a wide variety of substituted iodo- or bromo aryls (aryls suchas phenyl, naphthalene, etc.), heterocycles, alkyls, akenyls(Moreno-manas, M., et al., J. Org. Chem., 1995, 60, 2396), or alkynes.It can also undergo coupling with triflates of aryls, heterocycles, etc.(Fu, J. -m, Snieckus, V. Tet. Lett. 1990, 31, 1665-1668). Both of theabove reactions can also undergo carbonyl insertion in the presence ofan atmosphere of carbon monoxide (Ishiyama, et al., Tet. Lett. 1993, 34,7595). These nitro-containing compounds (155 and 157) can then bereduced to the corresponding amines either via catalytic hydrogenation,or via a number of chemical methods such as Zn/CaCl₂ (Sawicki, E. J OrgChem 1956, 21). The carbonyl insertion compounds (158) can also undergoreduction of the carbonyl group to either the CHOH or CH2 linkages bymethods already discussed (NaBH₄ or Et₃SiH, TFA, etc.). These amines canthen be converted to isocyanate 5 via the following methods (Nowakowski,J. J Prakt Chem/Chem-Ztg 1996, 338 (7), 667-671; Knoelker, H. -J. etal., Angew Chem 1995, 107 (22), 2746-2749; Nowick, J. S. et al., J OrgChem 1996, 61 (11), 3929-3934; Staab, H. A.; Benz, W.; Angew Chem 1961,73); to isothiocyanate 5 via the following methods (Strekowski L. etal., J Heterocycl Chem 1996, 33 (6), 1685-1688; Kutschy, P et al.,Synlett 1997, (3), 289-290); to carbamoyl chloride 11 (after 156 or 158is reductively aminated with an R² group) (Hintze, F.; Hoppe, D.;Synthesis (1992) 12, 1216-1218); to thiocarbamoyl chloride 11 (after 156or 158 is reductively aminated with an R² group) (Ried, W.; Hillenbrand,H.; Oertel, G.; Justus Liebigs Ann Chem 1954, 590); or just used as 9,or 10 (after 156 or 158 is reductively aminated with an R² group), insynthesizing the compounds of this invention by the methods depicted inScheme 1.

Likewise, protected aminobromobenzenes or triflates or protectedaminobromoheterocycles or triflates 159 (Scheme 25) may undergoSuzuki-type couplings with arylboronic acids or heterocyclic boronicacids (160). These same bromides or triflates 159 may also undergoStille-type coupling (Echavarren, A. M., Stille, J. K. J. Am. Chem.Soc., 1987, 109, 5478-5486) with aryl, vinyl, or heterocyclic stannanes163. Bromides or triflates 159 may also undergo Negishi-type couplingwith other aryl or heterocyclic bromides 164 (Negishi E. Accts. Chem.Res. 1982, 15, 340; M. Sletzinger, et al., Tet. Lett. 1985, 26, 2951).Deprotection of the amino group yields an amine with can be coupled tomake a urea and other linkers containing Z as described above and forScheme 1. Amino protecting groups include phthalimide, 2,4-dimethylpyrrole (S. P. Breukelman, et al. J. Chem. Soc. Perkin Trans. I, 1984,2801); N-1,1,4,4-Tetramethyldisilyl-azacyclopentane (STABASE) (S.Djuric, J. Venit, and P. Magnus Tet. Lett 1981, 22, 1787) and othersfamiliar to one skilled in the art.

Compounds where R⁷ and R⁸ are taken together to form ═NR^(8b) can besynthesized by the methods in Scheme 25a. Reacting 1 with nitrile a withCuCl catalysis forms amidine b where R^(8b) is H (Rousselet, G.;Capdevielle, P.; Maumy, M.; Tetrahedron Lett. 1993, 34 (40), 6395-6398).Note that the urea portion may be in final form or in precursor form(for example, a protected nitrogen atom; P=protecting group such asSTABASE, bis-BOC, etc., as was discussed previously) which may besubsequently elaborated into the compounds of this invention. Compoundsb may be also synthesized by reacting iminoyl chloride c withpyrrolidine/piperidine 1 to yield b where R^(8b) is not H (Povazanec,F., et al., J. J. Heterocycl. Chem., 1992, 29, 6, 1507-1512). Iminoylchlorides are readily available from the corresponding amide via PCl₅ orCCl₄/PPh₃ (Duncia, J. V. et al., J. Org. Chem., 1991, 56, 2395-2400).Again, the urea portion may be in final form or in precursor form.

Many amines are commercially available and can be used as 9, 10, or usedas precursors to isocyanates or isothiocyanates 5. There are numerousmethods for the synthesis of non-commercially available amines familiarto one skilled in the art. For example, aldehydes and ketones may beconverted to their O-benzyl oximes and then reduced with LAH to form anamine (Yamazaki, S.; Ukaji, Y.; Navasaka, K.; Bull Chem Soc Jpn 1986,59, 525). Ketones and trifluoromethylketones undergo reductive aminationin the presence of TiCl₄ followed by NaCNBH₄ to yield amines (Barney, C.L., Huber, E. W., McCarthy, J. R. Tet. Lett. 1990, 31, 5547-5550).Aldehydes and ketones undergo reductive amination with Na(AcO)₃BH asmentioned previously to yield amines (Abdel-Magid, A. F., et al. Tet.Lett. 1990, 31, (39) 5595-5598). Amines may also be synthesized fromaromatic and heterocyclic OH groups (for example, phenols) via theSmiles rearrangement (Weidner, J. J., Peet, N. P. J. Het. Chem., 1997,34, 1857-1860). Azide and nitrile displacements of halides, tosylates,mesylates, triflates, etc. followed by LAH or other types or reductionmethods yield amines. Sodium diformyl amide (Yinglin, H., Hongwen, H.Synthesis 1989 122), potassium phthalimide, and bis-BOC-amine anion canall displace halides, tosylates, mesylates, etc., followed by standarddeprotection methods to yield amines, procedures which are familiar toone skilled in the art. Other methods to synthesize more elaborateamines involve the Pictet-Spengler reaction, imine/immonium ionDiels-Alder reaction (Larsen, S. D.; Grieco, P. A. J. Am. Chem. Soc.1985, 107, 1768-69; Grieco, P. A., et al., J. Org. Chem. 1988, 53,3658-3662; Cabral, J. Laszlo, P. Tet. Lett. 1989, 30, 7237-7238; amidereduction (with LAH or diborane, for example), organometallic additionto imines (Bocoum, A. et al., J. Chem. Soc. Chem. Comm. 1993, 1542-4)and others all of which are familiar to one skilled in the art.

Compounds containing an alcohol side-chain alpha to the nitrogen of thepiperidine/pyrrolidine ring can be synthesized as shown in Scheme 25b.Only the piperidine case is exemplified, and it is to be understood byone skilled in the art that the alpha-substituted pyrrolidines may besynthesized by a similar route. It is also understood that appropriatesubstituents may be present on the piperidine/pyrrolidine ring. A4-benzylpiperidine 196 is protected with a BOC group. The BOC-piperidine197 is then metallated under conditions similar to those Beak, et al.(P. Beak and W. -K. Lee, J. Org. Chem. 1990, 55, 2578-2580, andreferences therein) and quenched with an aldehyde to yield alcohol 198.The metallation may also be done enantioselectively using sparteine (P.Beak, S. T. Kerrick, S. Wu, J. Chu J. Am. Chem. Soc. 1994, 116,3231-3239). This alcohol can be deprotonated with NaH and cyclized tocarbamate 198a which permits structural assignments of the erythro andthreo isomers. Deprotection with base yields aminoalcohol 199.Subsequent N-alkylation yields phthalimidoalkylpiperidine 201. It is tobe understood that the alkyl chain does not necessarily have to ben-propyl, but that n-propyl was chosen for demonstration purposes only.Deprotection of the phthalimido group with hydrazine yields amine 202.Finally, reaction with an isocyanate or via any of the previouslydescribed conditions described in Scheme 1 yields urea 203. If anisocyanate is used, the isocyanate can add twice to yield urea-carbamate204.

Compounds where Z=N—CN, CHNO₂, and C(CN)₂ can be synthesized by themethods shown in Scheme 25c. Thus amine 208 reacts with malononitrile207 neat or in an inert solvent at room temperature to the refluxtemperature of the solvent, or at the melting point of the solid/solidmixture, to yield malononitrile 206. This in turn can undergo reactionwith amine 205 under similar conditions stated just above to yieldmolononitrile 209. Likewise, a similar reaction sequence may be used tomake 212 and 215 [for Z=C(CN)₂], see for example P. Traxler, et al., J.Med. Chem. (1997), 40, 3601-3616; for Z=N—CN, see K. S. Atwal, J. Med.Chem. (1998) 41, 271; for Z=CHNO₂, see J. M. Hoffman, et al., J. Med.Chem. (1983) 26, 140-144).

EXAMPLES

The compounds of this invention and their preparation can be understoodfurther by the following working examples. These examples are meant tobe illustrative of the present invention, and are not to be taken aslimiting thereof.

Example 1

Part A: Preparation of4-benzyl-1-(3-N-phthalimido-n-prop-1-yl)piperidine

4-benzylpiperidine (8.0 g, 45.6 mmol, 1 eq),N-(3-bromopropyl)-phthalimide (13.5 g, 50.2 mmol, 1.1 eq), potassiumiodide (7.6 g, 45.6 mmol, 1 eq) and potassium carbonate (2.6 g, 91.3mmol, 2 eq) were refluxed in 125 mL of 2-butanone. The reaction wasworked up after 5 hours by filtering off the inorganic solids thenadding EtOAc and rinsing the organic layer 2× with water. The organiclayer was dried over magnesium sulfate then the solvent removed in vacuoto obtain an amber oil. The oil was purified by flash chromatography in100% EtOAc to remove impurities then 8:2 chloroform/methanol to isolate3.67 g of the product as a light amber oil. NMR(300 MHz, CDCl₃) δ8.00-7.80 (m, 2H); 7.80-7.60 (m, 2H); 7.35-7.10 (m, 3H); 7.08 (d, 2H,J=7 Hz); 3.76 (t, 2H, J=7 Hz); 2.83 (d, 2H, J=10 Hz); 2.45-2.30 (m, 4H);1.95-1.30 (m, 7H); 1.20-0.90 (m, 2H).

Part B: Preparaton of 4-benzyl-1-(3-amino-n-prop-1-yl)piperidine

4-benzyl-1-(3-N-phthalimido-n-prop-1-yl)piperidine (13.72 g, 37.9 mmol,1 eq.) was dissoved in 200 mL of EtOH at 25° C. under N₂, the anhydroushydrazine (2.38 mL, 75.7 mmol, 2 eq.) was added. The solution was thenrefluxed during which time a white precipitate formed. The reaction wasworked up after refluxing 4 hours by filtering off the solids. Thesolvent was removed in vacuo to obtain an oil which was re-rotovappedfrom toluene to remove excess hydrazine. Obtained an oil which wasstirred in Et₂O. Insoluble material was filtered then the solventremoved in vacuo to obtain 5.55 g of an amber oil as product. NMR (300MHz, CDCl₃) δ 7.40-7.21 (m, 2H); 7.21-7.05 (m, 3H); 2.92 (d, 2H, J=10Hz); 2.73 (t, 2H, J=7 Hz); 2.53 (d, 2H, J=7 Hz); 2.40-2.20 (m, 2H); 1.84(t of t, 2H, J=7,7 Hz); 1.75-1.10 (m, 9H).

Part C:N-(3-cyanophenyl)-N′-[3-[4-(phenylmethyl)-1-piperidinyl]propyl]urea

4-benzyl-1-(3-amino-n-prop-1-yl)piperidine (300 mg, 1.29 mmol, 1 eq) wasdissoved in THF at 25° C. under N₂ then 3-cyanophenyl isocyanate (186mg, 1.29 mmol, 1 eq) was added. TLC after 30 minutes shows the reactioncomplete. The solvent was removed in vacuo then the residue was purifiedover silica gel in 100% EtOAc to 8:2 chloroform/MeOHto yield 437 mg ofan amber oil as product. NMR (300 MHz, DMSO-d₆) δ 9.90-9.50 (m, 1H);9.32 (s, 1H); 7.93 (s, 1H); 7.59 (d, 1H, J=7 Hz); 7.43 (t, 1H, J=7 Hz);7.40-7.24 (m, 3H); 7.24-7.10 (m, 3H); 6.68 (t, 1H, J=7 Hz); 3.50-3.25(m, 2H); 3.25-3.07 (m, 2H); 3.07-2.90 (m, 2H); 2.90-2.60 (m, 2H);2.60-2.40 (m, 2H); 2.00-1.60 (m, 5H); 1.60-1.30 (m, 2H).

Example 2

Part A: Preparation of4-benzyl-1-carbomethoxymethyl-1-[3-(3-cyanophenylaminocarbonylamino)prop-1-yl]piperidinium

4-benzyl-1-[3-(3-cyanophenylaminocarbonylamino)prop-1-yl]piperidine (50mg, 0.133 mmol, 1 eq), was dissoved in acetone at 25° C. under N₂ thenmethyl bromoacetate (13 uL, 0.133 mmol, 1 eq),was added. After 16 hours,the solvent was removed in vacuo and the residue was purified oversilica gel in 100% EtOAc to 8:2 chloroform/MeOH to yield 50 mg of whitesolids as product. NMR (300 MHz, CD₃OD) δ 8.00-7.80 (m, 1H); 7.65-7.45(m, 1H); 7.45-7.33 (m, 1H); 7.33-7.05 (m, 6H); 4.50-4.25 (m, 2H);4.00-3.60 (m, 5H); 3.50-3.20 (m, 6H); 2.70-2.50 (m, 2H); 2.10-1.60 (m,7H).

Example 3

Part A: Preparation of 1-(t-Butoxycarbonyl)-3-piperidone

To a deep yellow solution of 1-benzyl-3-piperidone hydrochloride (3.00g, 1.33 mmol, 1 equiv) in methanol (100 mL) was added 10 wt. % (drybasis) palladium on activated carbon (600 mg) under a stream ofnitrogen. The resulting black suspension was deoxygenated by alternateevacuation and flushing with nitrogen (3×) followed by alternateevacuation and flushing with hydrogen (3×). The reaction suspension wasthen shaken vigorously under a hydrogen atmosphere of 55 psi. After 12hours, gravity filtration of the supsension and concentration of theresulting filtrate in vacuo yielded crude 3-piperidone as a viscouslight green oil. The oil was immediately treated with tetrahydrofuran(150 mL) and di-t-butyldicarbonate (4.73 g, 21.7 mmol, 0.98 equiv). Uponaddition of saturated aqueous sodium bicarbonate (25 mL), the oilcompletely dissolved to give a light yellow suspension. After stirringthe suspension vigorously for 2 hours, the now white suspension waspoured into aqueous hydrogen chloride (1N, 100 mL), and the layers wereseparated. The aqueous layer was extracted with ethyl acetate (3×70 mL),and the combined organic layers were washed with saturated aqueoussodium chloride (50 mL), dried over sodium sulfate, and filtered.Concentration of the resulting filtrate in vacuo yielded1-(t-butoxycarbonyl)-3-piperidone (3.79 g, 86%) as a white oily solid.¹H NMR (300 MHz, CDCl₃), δ:3.94 (s, 2H), 3.53 (t, 2H, J=6 Hz), 2.41 (t,2H, J=7 Hz), 1.92 (m, 2H), 1.41 (s, 9H)

Part B: Preparation of1′,3-(2H)-Dehydro-3-benzyl-1-(t-butoxycarbonyl)piperidine

To a flame-dried 100-mL flask charged with sodium hydride (60% wt.dispersion in mineral oil; 601 mg, 15.0 mmol, 2.3 equiv)) and1,2-dimethoxyethane (20 mL) was added benzyl diethylphosphite (3.42 g,3.13 mL, 15.0 mmol, 2.3 equiv) dropwise over a period of 5 min. After 10min, 1-(t-butoxycarbonyl)-3-piperidone was added in one portion to thepale yellow suspension. The flask was fitted with a relfux condensor,and the resulting yellow-gray suspension at heated under refluxconditions for 2 hrs. Upon cooling to 23° C., the reaction was pouredinto aqueous hydrogen chloride (0.20 N, 100 mL) and diethyl ether (75mL). The layers were separated and the aqueous layer was basified withsaturated aqueous sodium bicarbonate to pH 9. The aqueous layer wasextracted with diethyl ether (4×75 mL), and the combined organic layerswere dried over sodium sulfate. Filtration, concentration in vacuo, andpurification of the resulting residue by flash column chromatography (5%ethyl acetate in hexanes) afforded a mixture of the desired olefin (410mg, 23%) and the corresponding ethoxycarbamate (550 mg, 34%) as a clearoil. The ethoxycarbamate was removed in the subsequent step by flashcolumn chromatography. ¹H NMR (300 MHz, CDCl₃), δ: 7.30 (m, 2H), 7.18(m, 3H), 6.42 (s, 1H), 4.02 (s, 2H), 3.50 (t, 2H, J=6 Hz), 2.51 (t, 2H,J=5 Hz), 1.61 (m, 2H), 1.49 (s, 9H). MS (CI), m⁺/z: (M+H)⁺=274,[(M+H)⁺-(—C(O)OC(CH₃)₃)] 174.

Part C: Preparation of 1-(t-Butoxycarbonyl)-3-benzylpiperidine

To a solution of impure product (410 mg, 1.50 mmol) obtained in theprevious step in methanol (100 mL) was added 10 wt. % (dry basis)palladium on activated carbon (200 mg) under a stream of nitrogen. Theresulting black suspension was deoxygenated by alternate evacuation andflushing with nitrogen (3×) followed by alternate evacuation andflushing with hydrogen (3×). The reaction suspension was then shakenvigorously under a hydrogen atmosphere of 55 psi. After 12 hours,gravity filtration of the supsension and concentration of the resultingfiltrate in vacuo resulted in a pale yellow residue. Purification ofthis residue by flash column chromatography afforded1-(t-butoxycarbonyl)-3-benzyl-piperidine (407 mg, 99%) as a clear oil.¹H NMR (300 MHz, CDCl₃), δ:7.23 (m, 2H), 7.14 (m, 3H), 3.86 (m, 2H),2.75 (br m, 1H), 2.51 (m, 3H), 1.70 (br. m, 2H), 1.64 (br. m, 1H), 1.41(s, 9H), 1.34 (br. m, 1H), 1.09 (br. m, 1H). MS (CI), m⁺/z: (M⁺+1) 276,[(M+H)⁺-(—C(O)OC(CH₃)₃)]=176.

Part D: 3-Benzylpiperidine hydrochloride

To a solution of 1-(t-butoxycarbonyl)-3-benzylpiperidine (400 mg, 1.45mmol) in methanol (5 mL) was added hydrogen chloride in dioxane (4M, 15mL). The resulting yellow solution was stirred for 1 hr, at which timethe reaction was concentrated in vacuo to provide 3-benzylpiperidinehydrochloride (308 mg, 100%) as an amorphous solid. ¹H NMR (300 MHz,CD₃OD), δ:7.27 (m, 2H,), 7.19 (m, 3H), 3.29 (br. d, 1H, J=12 Hz), 3.20(br. d, 1H, J=12 Hz), 2.87 (br. t, 1H, J=12 Hz), 2.67 (m, 1H), 2.60 (d,2H, J=7 Hz), 2.08 (m, 1H) 1.70-1.87 (m, 3H), 1.26 (m, 1H). MS (CI),m⁺/z: (M+H)⁺=176.

Part E: Preparation ofN-(3-methoxyphenyl)-N′-[3-[3-[(phenyl)methyl]-1-piperidinyl]propyl]urea

The above compound was prepared by the methods similar to the onesemployed in Example 1, part C. ¹H NMR (300 MHz, CD₃OD), δ:7.29-7.13 (m,4H); 7/07 (d, 1H, J=9 Hz); 7.02 (m, 1H); 6.78 (d, 1H, J=9 Hz); 6.60 (d,1H, J=9 Hz); 3.77 (s, 3H); 3.30 (m, 2H); 2.80 (m, 2H); 2.53-2.32 (m,4H); 1.85-1.55 (m, 7H); 1.44-0.78 (m, 2H). MS (ESI), m⁺/z: (M+H)⁺=382.

Example 4

Part A: Preparation of a,a′-Dibromo-3-nitro-o-xylene

3-Nitro-o-xylene (10.0 g, 66.14 mmol, 1.00 eq), N-bromosuccinimide(24.14 g, 135.6 mmol, 2.05 eq), and benzoyl peroxide (0.8 g, 3.30 mmol,0.5 eq) were refluxed under N₂ in 200 ml of carbon tetrachloride. Thereaction was worked up after two days by washing with 3×100 ml of water.The organic phase was dried over sodium sulfate, then the solvent wasremoved in vacuo to obtain an amber oil. The oil was purified by flashchromatography on a 8 cm×20 cm quartz column, eluting with 7.5%EtOAc/Hexanes to yield 4.46 g of product as a sticky solid. NMR (300MHz, CDCl₃) δ 7.88 (d, 1H, J=7 Hz), 7.64 (d, 1H, J=7 Hz), 7.48 dd, 1H,J=8 Hz), 4.86 (s, 2H), 4.69(s, 2H).

Part B: Preparation of1,3-Dihydro-4′-[4-fluorophenylmethyl]-4-nitro-spiro[2H-isoindole-2,1′-piperidinium]bromide

4-Fluorobenzylpiperidine (0.94 g, 4.86 mmol, 1.0 eq),a,a′-dibromo-3-nitro-o-xylene (1.50 g, 4.86 mmol, 1.0 eq), and sodiumcarbonate (2.57 g, 24.3 mmol, 5.0 eq) were combined in 20 ml THF andstirred at 25° C. under N₂, during which time a white solid precipitatedfrom the reaction mixture. The reaction was worked up after 22 hours byfiltering the solids and rinsing with THF. The solids were dissolved inmethanol and applied to a 3.5 cm×5 cm quartz column via silica plug. Theproduct was eluted with 20% MeOH/CHCl₃ to yield 1.04 g of a white foam.NMR (300 MHz, CD₃OD) δ 8.27 (d, 1H, J=8 Hz), 7.84-7.80 (m, 1H),7.75-7.69 (m, 1H), 7.23 (m, 2H), 7.01 (dd, 2H, J=8 Hz, 8 Hz), 5.38-5.37(m, 2H), 5.09 (s, 1H), 5.04 (s, 1H), 3.80-3.72 (m, 2H), 3.65-3.54 (m,2H), 2.71-2.68 (m, 2H), 2.05-1.75 (m, 5H).

Part C: Preparation of 4-Amino-1,3-dihydro-4′-[4-fluorophenylmethyl]-spiro[2H-isoindole-2,1′-piperidinium]bromide

1,3-Dihydro-4′-[4-fluorophenylmethyl]-4-nitro-spiro[2H-isoindole-2,1′-piperidinium]bromide (1.03 g, 2.46 mmol, 1.0 eq), zinc (5.32 g, 81.5 mmol, 33.0 eq),and calcium chloride (0.18 g, 1.60 mmol, 0.65 eq) were refluxed under N₂in 25 ml of a 78% ethanol/water solution. The reaction was worked upafter 5 hours by filtering through Celite® and rinsing the cake withmethanol. The filtrate was concentrated in vacuo to a mixture of waterand an amber oil. The mixture was dissolved in 50 ml of 2-propanol, andconcentrated in vacuo to remove excess water. The resulting yellow foamwas dissolved in methanol and applied to a 3.5 cm×5 cm quartz column viasilica plug. The product was eluted with 20% MeOH/CHCl₃ to yield 0.81 gof a yellow foam. NMR (300 MHz, DMSO) δ 7.27-7.05 (m, 5H), 6.61-6.53 (m,2H), 5.43-5.41 (m, 2H), 4.80 (bs, 1H), 4.74 (bs, 2H), 4.63 (bs, 1H),3.62-3.43 (m, 4H), 2.60 (bd, 2H, J=7 Hz), 1.98-1.59 (m, 5H).

Part D: Preparation ofN-[1,3-Dihydro-4′-[4-fluorophenyl-methyl]spiro[2H-isoindole-2,1′-piperdinium-4-yl]-N′-4-fluorophenylureabromide

4-Amino-1,3-dihydro-41-[4-fluorophenylmethyl]-spiro[2H-isoindole-2,1′-piperidinium]bromide (0.33 g, 0.84 mmol, 1.0 eq), and 4-fluorophenyl isocyanate (0.23g, 1.69 mmol, 2.0 eq) were combined in 3 ml DMF and stirred at 25•Cunder N₂. The reaction was worked up after 22 hours by removing thesolvent in vacuo, dissolving the residue in methanol, and applying themixture to a 3.5 cm×15 cm quartz column via silica plug. The product waseluted with 10% MeOH/CHCl₃ to yield 65 mg of a yellow foam. NMR (300MHz, DMSO) δ 9.18 (s, 1H), 9.00 (s, 1H), 7.49-7.43 (m, 2H), 7.41-7.34(m, 2H), 7.26-7.21 (m, 2H), 7.17-7.10 (m, 5H), 4.94 (s, 2H), 4.80 (s,2H), 3.63-3.45 (m, 4H), 2.61 (bd, j=7 Hz), 1.91-1.62 (m, 5H)

Example 5

Part A. Preparation of4-benzyl-1-(3-hydroxy-3-phenylprop-1-yl)piperidine

To a flame-dried 3-neck flask under a N₂ atmosphere with a magneticstirring bar, 4-benzylpiperidine (5.00 mL, 28 mmol, 1 eq), DBU (42 μL,0.28 mmol, 0.01 eq), and THF (100 mL) were added, mixed, and cooled to−15° C. using a CCl₄/CO₂(s) bath. Acrolein (1.87 mL, 28 mmol, 1 eq) wasthen syringed in slowly during 10 minutes maintaining the temp. at −15°C. After 0.5 hours at −15° C., phenylmagnesium chloride (2.0 M, 14.0 mL,28 mmol, 1 eq) was syringed in slowly and the contents allowed to slowlywarm to room temperature and then stirred for 48 h. The reaction wasworked up by adding 0.1 N NaOH and EtOAc (200 mL each). The viscousmagnesium salts were suction filtered through fiberglass filter paper.The layers were separated and the aqueous layer was extracted again withethyl acetate (2×200 mL). The organic layers were combined, washed withbrine (1×200 mL), dried (MgSO₄) and the solvent removed in vacuo toyield 7.39 g of an amber oil. Flash chromatography in 100% ethylactetate yielded 2.48 g of an orange oil. NMR (CDCl₃) δ 7.40-7.10 (m,10H); 4.93 (d of d, 1H, J=3,7 Hz); 3.12-2.96 (m, 2H); 2.68-2.46 (m, 4H);2.01 (t of d, 1H, J=2, 10 Hz); 1.86-1.26 (m, 8H). ESI MS detects(M+H)⁺=310.

Part B: Preparation of 4-benzyl-1-(3-azido-3-phenylprop-1-yl)piperidine

The product from part A (209 mg, 0.675 mmol, 1 eq), DBU (123 mg, 0.810mmol, 1.2 eq), diphenylphosphoryl azide (0.175 mL, 0.810 mmol, 1.2 eq),and toluene (1.0 mL) were mixed and stirred overnight at roomtemperature under a N₂ atmosphere. The reaction was then worked up byadding ethyl acetate (50 mL), washing with water (3×25 mL), followed bywashing with brine (1×25 mL), drying (MgSO₄) and removing the solvent invacuo to yield 277 mg of an amber oil. Flash chromatography in 1:1hexane/ethyl acetate yielded 84 mg of product as an oil. NMR (CDCl₃) δ7.41-7.09 (m, 10 H); 4.56 (t, 1H, J=7 Hz); 3.83 (m, 2H); 2.52 (d, 2H,J=7 Hz); 2.32 (t, 2H, J=7 Hz); 2.30-1.77 (m, 5H); 2.59 (m, 2H); 1.98 (m,1H); 1.39-1.26 (m, 4H). IR (neat) 2095 cm⁻¹.

Part C: Preparation of 4-benzyl-1-(3-amino-3-phenylprop-1-yl)piperidine

The compound from part B (100 mg), 10% Pd on carbon (120 mg), andmethanol (100 mL) were carefully combined in a flask under a N₂atmosphere. The contents were then submitted to 1 atm of H₂ beingdelivered via a sparge tube for 0.5 h at room temperature. Filtration ofthe contents through Celite® and removal of the solvent in vacuo yielded70 mg of product. NMR (CDCl₃) (key peak only) δ3.94 (t, 1, J=7 Hz).NH₄—CI MS detects (M+H)⁺=309.

Part D:N-(3-cyanophenyl)-N′-[3-[4-(phenylmethyl)-1-piperidinyl]-1-phenylpropyl]urea

The compound from Part C (57 mg, 0.185 mmol, 1 eq) was mixed and stirredwith 3-cyanophenylisocyanate 26.6 mg, 0.185 mmol, 1 eq) in THF (1 mL)overnight at room temperature under a N₂ atmosphere. The solvent wasremoved in vacuo and the residue flash chromatographed on silica gel in3:1 to 1:1 hexane/ethyl acetate to 100% ethyl acetate to yield 44.3 mgof a yellow oil. NMR (CDCl₃) δ7.58 (s, 1H); 7.52 (d, 1H, J=9 Hz); 7.42(s, 1H); 7.30-7.17 9 m, 8H); 7.12 (m, 3H); 4.82 (m, 1H); 2.97-2.80 (m,3H); 2.52 (d, 2H, J=7 Hz); 2.35 (m, 2H); 2.05-1.85 (m, 4H); 1.81-1.60(m, 2H); 1.54 (m, 1H); 1.25 (m, 1H). ESI MS detects (M+H)⁺=453.

Example 6

Part A: Preparation of 2-benzyloxycarbonylamino-1-phenyl-3-butene.

To a stirred suspension of methyltriphenylphosphonium bromide (10.72 g,0.03 moles) in 100 mL of dry tetrahydofuran at −78° C. was addeddropwise 1.6M n-butyl lithium (17.5 mL, 0.028 moles), and the mixturewas stirred for 0.5 hrs at −78˜−20° C. Then was added a solution ofN-Cbz-phenylalaninal (5.67 g, 0.02 moles) in 50 mL of drytetrahydrofuran, and the mixture was stirred for 16 hrs at roomtemperature. After addition of saturated NH4Cl (50 mL) the mixture wasextracted with EtOAc, and the extract was washed with water and brine.It was dried over Na2SO4 and evaporated to give an oily residue. Thecrude product was purified by column chromatograpy on silica gel withelution by 5:95 EtOAc-hexane to give pure2-benzyloxycarbonylamino-1-phenyl-3-butene.

Part B: Preparation of2-benzyloxycarbonylamino-1-phenyl-3,4-epoxy-butane.

To a stirred solution of 2-benzyloxycarbonylamino-1-phenyl-3-butene(1.43 g, 5.08 mmoles) in 20 mL of CH2Cl2 was added 3-chloroperoxybenzoicacid (2.19 g, 60%, 7.62 mmoles) in several portions, and the mixture wasstirred at room temperature for 30 hrs. After addition of EtOAc (60 mL),the mixture was washed with saturated NaHCO3 and brine, and the organiclayer was dried over Na2SO4. Evaporation of the solvent afforded an oilyresidue. The crude product was purified by column chromatography onsilica gel with elution by 2:8 EtOAc-hexane to give pure2-benzyloxycarbonylamino-1-phenyl-3,4-epoxy-butane.

Part C: Preparation of2-benzyloxycarbonylamino-4-[4-(4-fluorophenyl)methyl-1-piperidinyl]-1-phenyl-butan-3-ol.

A solution of 4-(4-fluorophenyl)methyl-piperidine (0.515 g, 2.314mmoles) and 2-benzyloxycarbonylamino-1-phenyl-3,4-epoxy-butane (0.688 g,2.314 mmoles DMF was stirred for 4 hours at 100° C. and cooled to roomtemperature. After addition of EtOAc (30 mL), the mixture was washedwith water (2×) and brine. The oranic solution was dried over Na2SO4,and evaporated to give an oily residue. It was then purified by passingthrough a plug of silica gel with elution by EtOAc to give pure product.

Part D: Preparation of2-amino-4-(4-(4-fluorophenyl)methyl-1-piperidinyl)-1-phenyl-butan-3-ol.

The above product was dissolved in 10 mL of ethanol, and was added 0.1 gof 10% Pd on carbon. The mixture was stirred under hydrogen (1 atm) for8 hours, and filtered through Celite. Evaporation of the solvent gavethe titled product as solid (0.662 g).

Part E: Preparation ofN-(3-cyanophenyl)-N′-[1-benzyl-2-hydroxy-3-[4-(4-fluorophenylmethyl)-1-piperidinyl]propyl]urea

To a solution of2-amino-4-[4-(4-fluorophenyl)methyl-1-piperidinyl]-1-phenyl-butan-3-ol(50 mg, 0.14 mmoles) in 2.5 mL of dry THF was added 3-cyanophenylisocyanate (20.2 mg, 0.14 mmoles) and the mixture was stirred for 15minutes at room temperature. Then the solvent was evaporated off to givean oily residue. It was purified by column chromatography on silica gelwith elution by EtOAc to give pure titled compound as an amorphoussolid. MS (ES+) for C₃₀H₃₃FN₄O₂:501.

The following examples were prepared by the procedures previouslydescribed in Schemes 1-25, Examples 1-6 and/or by procedures familiar toone skilled in the art.

TABLE 1*

Ex # Core G R3 M + 1  7 a Ph 3-CO2Et—Ph 410  8 a Ph 3-I—Ph 464  9 a Ph1-adamantyl 396  10 a Ph 3-OCH3—Ph 368  11 a Ph Ph 338  12 a Ph 4-F—Ph356  13 a Ph 4-CO2Et—Ph 410  14 a Ph 4-CN—Ph 363  15 b Ph 1-adamantyl410  16 b Ph 2-F-5-CF3—Ph 438  17 b Ph 2-naphthyl 402  18 b Ph2-F-5-NO2—Ph 415  19 b Ph 4-N(CH3)2—Ph 395  20 b Ph 2-NO2—Ph 397  21 bPh 2-C2H5—Ph 380  22 b Ph 4-CF4—Ph 420  23 b Ph 3,5-diCF3—Ph 488  24 bPh 3-CO2Et—Ph 424  25 b Ph 3-CN—Ph 377  26 b Ph 4-OBn—Ph 458  27 b Ph2-Ph—Ph 428  28 b Ph 2-BrPh 431  29 b Ph 4-I—Ph 478  30 b Ph 3-I—Ph 478 31 b Ph 4-OEt—Ph 396  32 b Ph 4-nBu—Ph 408  33 b Ph 4-nBuO—Ph 424  34 bPh CH(Bn)CO2Et 452  35 b Ph CH(iPr)CO2Et 404  36 b Ph nC8H17 388  37 bPh 3-OCH3—Ph 382  38 b Ph Ph 352  39 b Ph 4-CO2Et—Ph 424  40 b Ph 4-F—Ph370  41 b Ph 2-Phenyl-cyclopropyl 392  42 b Ph 2-OCH3—Ph 382  43 b Ph4-OCH3—Ph 382  44 b 4-F—Ph 3-CN—Ph 395  45 b 4-F—Ph 4-F—Ph 388  46 b4-F—Ph 4-CO2Et—Ph 442  47 b 3,4-OCH2O—Ph 3-CN—Ph 421  48 b 4-F—Ph3-OCH3—Ph 400  49 b 3,4-OCH2O—Ph 3-CO2Et—Ph 468  50 b 3,4-OCH2O—Ph3-OCH3—Ph 426  51 b 4-OCH3—Ph 3-OCH3—Ph 412  52 b 4-OCH3—Ph 4-F—Ph 400 53 b Ph 4-CN—Ph 377  54 b 3,4-OCH2O—Ph 4-F—Ph 414  55 b 4-OCH3—Ph4-CN—Ph 407  56 b 2,4-diF—Ph 4-F—Ph 406  57 b 2,4-diF—Ph 3-OCH3—Ph 418 58 b 2,4-diF—Ph 3-CN—Ph 413  59 b 3-CF3—Ph 4-F—Ph 438  60 b 3-CF3—Ph3-OCH3—Ph 450  61 b 4-F—Ph CH2Ph 384  62 b 4-F—Ph CH2CH2Ph 398  63 b4-F—Ph 2-F—Ph 388  64 b 4-F—Ph 3-F—Ph 388  65 b 4-F—Ph cyclohexyl 376 66 b 4-F—Ph iPr 336  67 b 4-F—Ph 2-phenyl-cyclopropyl 410  68 b4-CF3—Ph 3-CN—Ph 445  69 b 3-CF3—Ph 3-CN—Ph 445  70 b 4-CH3—Ph 3-OCH3—Ph396  71 b 4-CH3—Ph 3-CN—Ph 391  72 b 4-Cl—Ph 3-CN—Ph 411  73 b 4-CF3—Ph4-CO2Et—Ph 492  74 b 3-OCH3—Ph 3-OCH3—Ph 412  75 b 3-OCH3—Ph 3-CN—Ph 407 76 b 4-CO2CH3—Ph 3-OCH3—Ph 440  77 b 4-CO2CH3—Ph 3-CN—Ph 435  78 b4-CO2CH3—Ph 4-F—Ph 428  79 b 4-CO2CH3—Ph 4-CO2CH3—Ph 482  80 b 4-CF3—Ph4-F—Ph 438  81 b 4-CF3—Ph 3-OCH3—Ph 450  82 b 3-OCH3—Ph 4-F—Ph 400  83 b3-OCH3—Ph 4-CO2Et—Ph 454  84 b 2-F—Ph 3-CN—Ph 395  85 b 3-OCH3—Ph 3-F—Ph400  86 b 2-F—Ph 3-OCH3—Ph 400  87 b 3-OCH3—Ph 3-CO2Et—Ph 454  88 b2-F—Ph 3-F—Ph 388  89 b 2-F—Ph 4-F—Ph 388  90 b 2-F—Ph 3-CO2Et—Ph 442 91 b 3-F—Ph 3-CN—Ph 395  92 b 3,4-diF—Ph 3-CN—Ph 413  93 b 3,4-diF—Ph3-OCH3—Ph 418  94 b 4-Cl—Ph 4-F—Ph 404  95 b 4-Cl—Ph 3-OCH3—Ph 416  96 b2-F—Ph 4-CO2Et—Ph 442  97 b 3-F—Ph 3-OCH3—Ph 400  98 b 3-F—Ph 4-F—Ph 388 99 b 3-F—Ph 4-CO2Et—Ph 442 100 b 3,4-diF—Ph 4-F—Ph 406 101 b 3-Cl—Ph3-CN—Ph 411 102 b 4-F—Ph 3-COCH3—Ph 412 103 b 3,5-diF—Ph 3-CN—Ph 413 104b 3,5-diF—Ph 3-OCH3—Ph 418 105 b 4-F—Ph 4-COCH3—Ph 412 106 b 1-naphthyl3-CN—Ph 427 107 b 1-naphthyl 4-F—Ph 420 108 b 1-naphthyl 3-OCH3—Ph 432109 b 3-CH3—Ph 3-CN—Ph 391 110 b 3-CH3—Ph 4-F—Ph 384 111 b 3-CH3—Ph3-OCH3—Ph 396 112 b 4-F—Ph 2-iPr—Ph 412 113 b 4-F—Ph 2-CF3—Ph 438 114 b4-F—Ph 3-Cl—Ph 404 115 b 4-F—Ph 3-CF3—Ph 438 116 b 4-F—Ph 4-Ph—Ph 446117 b 4-F—Ph 2-Cl—Ph 404 118 b 4-F—Ph 2,4-diF—Ph 406 119 c Ph 3-CO2Et—Ph424 120 c Ph 3-CN—Ph 377 121 c Ph 4-F—Ph 370 122 c Ph Ph 352 123 c Ph1-adamantyl 410 124 c Ph 4-CO2Et—Ph 424 125 c 4-F—Ph Ph 370 126 c 4-F—Ph3-CN—Ph 395 127 c 4-F—Ph 1-adamantyl 428 128 c 4-F—Ph 3-OCH3—Ph 400 129c 4-F—Ph 3-CO2Et—Ph 442 130 c 4-F—Ph 4-F—Ph 388 130a c 4-F—Ph 3-COCH3—Ph412 131 c 2-F—Ph Ph 370 132 c 2-F—Ph 3-CN—Ph 395 133 c 2-F—Ph 3-OCH3—Ph400 134 c 2-F—Ph 4-F—Ph 388 135 c 3-F—Ph 3-OCH3—Ph 400 136 c 3-F—Ph3-CN—Ph 395 137 c 2,4-diF—Ph 3-CN—Ph 413 138 c 2,4-diF—Ph 3-OCH3—Ph 418139 c 2,4-diF—Ph Ph 388 140 c 2,4-diF—Ph 4-F—Ph 406 141 c 2,4-diF—Ph3-COCH3—Ph 430 142 d Ph 3-CN—Ph 391 143 d Ph 3-CO2Et—Ph 438 144 d Ph3-I—Ph 492 145 d Ph 4-OCH2Ph—Ph 472 146 d Ph 1-adamantyl 424 147 d Ph3-OCH3—Ph 396 148 d Ph Ph 366 149 d Ph 4-F—Ph 384 150 d Ph 4-CO2Et—Ph438 151 d Ph 4-CN—Ph 391 152 e 4-F—Ph Ph 356 153 e 4-F—Ph 3-CN—Ph 381154 e 4-F—Ph 3-OCH3—Ph 386 155 e 4-F—Ph 4-F—Ph 374 156 e 4-F—Ph3-CO2Et—Ph 428 157 e 4-F—Ph 4-CO2Et—Ph 428 158 e 4-F—Ph 1-adamantyl 414159 f 4-F—Ph 3-CN—Ph 411 160 f 4-F—Ph 3-OCH3—Ph 416 161 j Ph Ph 458 162j Ph 3-CN—Ph 483 163 j Ph 3-OCH3—Ph 488 164 j 4-F—Ph 3-OCH3—Ph 506 165 j4-F—Ph 4-F—Ph 494 166 j 4-F—Ph 1-adamantyl 534 167 l Ph 3-OCH3—Ph 458168 l Ph 1-adamantyl 486 169 c imidazol-1-yl 3-OCH3—Ph 372 *Allstereocenters are (+/−) unless otherwise indicated

TABLE 2**

Ex # Y Z R4 X R_(5a) R_(5b) R_(5c) R1 R2 170 H H — — H H H H Ph 171 H H— — H H H H CH3 172 H 3-OCH3 CH2Ph Br H H H H H 173 H 3-CN — — CO2Et H HH H 174 H 3-OCH3 CH3 I H H H H H 175 H 3-CN CH3 I H H H H H 176 H 3-CNCH2Ph Br H H H H H 177 H 3-CN — — H H H CH2Ph H 178 H 3-CN — — H H H EtH 179 H 4-F CH3 I H H H H H 180 H 4-F CH2Ph Br H H H H H 181 H 4-FCH2CO2CH3 Br H H H H H 182 H 3-CN CH2CN Br H H H H H 183 H 3-CN CH2COPhBr H H H H H 184 H 2-OCH3 CH3 I H H H H H 185 H 4-OCH3 CH3 I H H H H H186 F 3-CN CH3 I H H H H H 187 H 3-CN — — H H H H H 188 H 3-OCH3 O — H HH H H 189 H 3-OCH3 — — CH2Ph 190 F 3-CN CH3 I H H H H H 191 F 3-COCH3 —— H CH2Ph H H H 192 F 4-F—Ph — — H CH2Ph H H H 193 F 3-OCH3 — — H CH2PhH H H 194 H 3-OCH3 — — H H H CH2Ph H 195 H 3-CN — — H H H CH2Ph H **Allcompounds are amorphous unless otherwise indicted.

TABLE 3**

Ex # Core Y Z X 196 n H 3-CN Br 197 n H 3-CN Br 198 n H 4-F Br 199 n H4-F Br 200 n F 3-CN Br 201 n F 3-CN Br 202 n F 3-OCH3 Br 203 n F 3-OCH3Br 204 o F 4-F Br 205 o F 4-F Br 206 o F 3-OCH3 Br 207 o F 3-OCH3 Br 208o F 3-CN Br 209 o F 3-CN Br **All compounds are amorphous unlessotherwise indicted.

The compounds of the present invention in which E contains ring A can beprepared in a number of ways well known to one skilled in the art oforganic synthesis. As shown in Scheme 26, 4-benzyl piperidine isN-alkylated with an alkylating agent, such as 165 (2-nitro-benzylbromide (X=Br, R¹⁴=H), Scheme 26) to give the N-benzyl compound 166. Thenitro group of 166 is then reduced using catalytic hydrogenation to givethe corresponding aniline 167. The aniline can be converted to thecarbamate 168 using chloro-phenyl formate. The carbamate 168 can then bereacted with various amines to give the urea 169. Alternatively, theaniline 167 can be reacted with the appropriate isocyanates to give theurea 169 directly. The saturated ring analogs can also be used. Forexample, 4-benzyl piperidine can be alkylated with the urea mesylate185. Scheme 30) to give corresponding cyclohexyl derivative 186.

As shown in Scheme 27, 4-benzyl piperidine can also be N-alkylated withthe phenacyl bromide 170 to give the nitro ketone 171. The nitro groupof 171 is then reduced using catalytic hydrogenation to give thecorresponding aniline 172. The aniline 172 can be reacted with theappropriate isocyantes to give the ketone urea 173. The ketone of 173can be reduced with NaBH₄ to give the alcohol 174.

Alternatively, the epoxide 175 (R¹⁴=H) can be opened with the 4-benzylpiperidine to give the corresponding nitro benzyl alcohol which ishydrogenated to give the aniline alcohol 176. The aniline 176 may betreated with various isocyanates to give the urea alcohols 174.

The 4-benzyl piperidine can also be N-alkylated with 3-cyanobenzylbromide (177, Scheme 28) to give the cyano analog 178. The cyano groupis reduced using Raney nickel to give the corresponding benzyl amine179. Treatment of 179 with isocyanates gives the urea 180.

As shown in Scheme 29, treatment of 3-cyano aniline withphenylisocyanate gives the urea 182. The cyano group of 182 is convertedto the imidate 183 by HCl/ethanol. Reaction with 4-benzyl piperidine inethanol then gives the amidine 184.

The saturated ring analogs can also be synthesized using analogousprocedures as outlined in Schemes 30 and 31. For example, 4-benzylpiperidine can be alkylated with the urea mesylate 185 (Scheme 29) togive corresponding cyclohexyl derivative 186. Alternatively, startingwith the enantiomerically pure amino alcohol 187 [J. Am. Chem. Soc.1996, 118, 5502-5503 and references therein] one can protect thenitrogen to give the N-Cbz alcohol 188. Swern oxidation of the alcoholgives the aldehyde 189. Reductive amination with piperidine analogsgives the cyclohexyl methyl-1-piperidinyl analogue 190. The Cbz group isremoved by catalytic hydrogenation to give the free amine 191, which istreated with a phenylisocyanate to give the desired urea analogue 192.Several examples using these synthetic methods are listed in Table 3aand Table 3.1.

The following examples were synthesized using the methods outlined inSchemes 26-31a. These examples are meant to be illustrative of thepresent invention, and are not to be limiting thereof.

Example 218N-[1-(phenylmethyl)4-piperidinyl]-N′-[2-[[4-(phenylmethyl)-1-piperidinyl]-methyl]phenyl]urea.

A solution of 4-benzylpiperidine (1.75 g, 10 mmol) in 25 mL of DMF wastreated with 2-nitrobenzyl bromide (2.16 g, 10 mmol) and K₂CO₃ (1.38 g,10 mmol) and the reaction mixture stirred at room temperature for 2 h.The mixture was diluted with water and extracted into ethyl acetate. Theorganic extracts were washed successively with water and brine, and theorganic solvent removed under vacuum on a rotary evaporator to give 166(Scheme 26, R¹⁴=H) as a yellow oil.

The oil was re-dissolved in ethyl acetate (50 ml) and treated with 10%Pd/C and hydrogenated at 50 psi hydrogen at room temperature for 40 min.The solution was then filtered and the solvent removed under vacuum togive the aniline 167 as a white solid. The aniline was purified bychromatography (MPLC, 40% ethyl acetate/hexane; silica gel) to give 2.0g of aniline 167 as a white solid.

A solution of aniline 167 (1.2 g, 4.3 mmol) in THF was treated with Et₃N(1.0 g, 10 mmol) and cooled in an ice bath to 0° C. Chlorophenyl formate(0.71 g, 4.5 mmol) was added to the mixture and stirred for 1 h. Themixture was diluted with water and extracted into ethyl acetate. Theextracts were washed with water and brine, and the solvent removed undervacuum to give the phenyl carbamate 168 as an off-white solid. The crudeproduct was used without further purification.

A solution of phenylcarbamate 168 (0.2 g, 0.5 mmol) in DMF is treatedwith 4-amino-1-benzylpiperidine (95 mg, 0.5 mmol) and K₂CO₃ (138 mg, 1mmol) and the mixture was heated at 50° C. for 2 h. The mixture wasdiluted with water and extracted into ethyl acetate. The extracts werewashed with water and brine, and the solvent removed under vacuum. Theresidue was purified by chromatography (MPLC, 0-25% MeOH/ethyl acetate;silica gel) to give 200 mg of the target compound as a white solid. esims: (M+H)⁺=497.

Example 219N-(2,5-difluorophenyl)-N′-[2-[[4-(phenylmethyl)-1-piperidinyl]-methyl)phenyl]urea

A solution of aniline 167 (Scheme 26; (R¹⁴=H)) (140 mg, 0.5 mmol) in THFis treated with 2,5-difluoro-isocyanate (80 mg, 0.5 mmol) at roomtemperature for 1 h. The solvent is removed under vacuum and the residuewas purified by chromatography (MPLC, 20% EtOAc/Hexane, silica gel) togive the desired urea as a white solid. esi ms: (M+H)⁺=436.

Example 220N-(2,5-difluorophenyl)-N′-[[3-[[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]methyl]urea

A solution of 4-benzylpiperidine (1.75 g, 10 mmol) in 25 mL of DMF wastreated with 3-cyanobenzyl bromide 177 (1.96 g, 10 mmol) and K₂CO₃ (2.76g, 20 mmol) and the reaction mixture stirred at room temperature for 2h. The mixture was diluted with water and extracted into ethyl acetate.The organic extracts were washed successively with water and brine, andthe organic solvent removed under vacuum on a rotary evaporator to give178 (Scheme 28) as a yellow oil.

To a suspension of Raney nickel (2.0 g) in EtOH (saturated withNH_(3(gas))) was added crude 178 (Scheme 28) (1.45 g, 5 mmol) andhydrogenated at 50 psi for 3 days. The solution was then filtered andthe solvent removed under vacuum to give the amine 179 as a yellow oil.A solution of amine 179 (200 mg, 0.68 mmol) in THF is treated with2,5-difluoroisocyanate (115 mg, 0.74 mmol) at room temperature for 1hour. The solvent is removed under vacuum and the residue is washed with1 NaOH and water to give the desired urea as a white solid. esi ms:(M+H)⁺=450.

Example 221N-(2,5-difluorophenyl)-N′-[2-[[4-(phenylmethyl)-1-piperidinyl]acetyl]phenyl]urea

To an ice cold solution of 2-bromo-2′-nitro-acetophenone 170 (2.4 g, 10mmol) in DMF is added 4-benzylpiperidine (1.75 g, 10 mmol) and stirredfor 30 min. The solution was poured into a mixture of K₂CO₃ (1.38 g, 10mmol) in water/ice and extracted into ethyl acetate. The ethyl acetateextract was washed several times with water. The resultant ethyl acetatesolution of crude nitroketone 171 is treated with 10% Pd/C andhydrogenated at 50 psi hydrogen at room temperature for 40 min. Thesolution was then filter, the solvent removed under vacuum, and theresidue purified by chromatography (MPLC, 30% ethyl acetate/hexane;silica gel) to give 1.8 g of aniline 172 as a tan/brown solid.

A solution of aniline 172 (Scheme 27) (310 mg, 1.0 mmol) in THF istreated with 2,5-difluoroisocyanate (160 mg, 1.0 mmol) at roomtemperature for 1 h. The solvent is removed under vacuum and the residueis purified by chromatography (MPLC, 20% EtOAc/Hexane, silica gel) togive 420 mg of the desired urea-ketone 173 as a white solid. esi ms:(M+H)⁺=464.

Example 222N-(2,5-difluorophenyl)-N′-[2-[2-[4-(phenylmethyl)-1-piperidinyl]-1-hydroxyethyl]phenyl]urea

A solution of the urea-ketone 173 (260 mg, 0.56 mmol) in MeOH is treatedwith NaBH₄ (400 mg, 11 mmol) at room temp for 1 hour. The solvent isremoved under vacuum and the residue is treated with 1 N NaOH andextracted into EtOAc. The extracts are washed with water, brine and thesolvent removed under vacuum to give the desired alcohol 174 as a whitesolid. esi ms: (M+H)⁺=466.

Example 223N-[3-[imino-[4-(phenylmethyl)-1-piperidinyl]methyl]phenyl]-N′-phenylurea

A solution of 3-cyanoaniline (3.54 g, 30 mmol) in THF is treated withphenylisocyanate (3.58 g, 30 mmol) at room temperature for 1 h. Thesolvent is removed under vacuum and the residue is titurated with hexaneto give 7 grams of urea 182 (Scheme 29) as a white solid. Urea 182 (1.0g, 4.2 mmol) is dissolved in EtOH, cooled in an ice bath while HCl isbubbled-in for 20 min. The solution is left standing at room temperaturefor 24 h. The solvent is removed under vacuum to give 1.1 g of theimidate 183 as a white solid. The crude imidate (0.5 g, 1.8 mmol) wasdissolved in EtOH and treated with 4-benzyl-piperidine (1.8 g, 10 mmol)at room temperature for 2 days. The solvent was removed under vacuum andthe residue was purified by chromatography (MPLC, 0 to 30% MeOH/EtOAc,silica gel) to give 200 mg of the desired amidine 184 (Scheme 29) as awhite solid. esi ms: (M+H)⁺=413.

Example 416 N-(3-methoxyphenyl)-N′-[(1R,2S)-2-[[(4-phenylmethyl)piperidinyl]methyl]cyclohexyl]urea

Step a: To a solution of (R,R) amino alcohol 187 [J. Am. Chem. Soc.1996, 118, 5502-5503 and references therein] (1.9 g, 14.7 mmol) inCH₂Cl₂ (50 mL) is added 50 ml of an aqueous solution of Na₂CO₃ (2.4 g,28.9 mmol). While stirring, benzyl chloroformate (2.51 g, 14.7 mmol) isadded and the mixture is stirred at room temperature for 1 h. Theorganic layer is separated and washed with water and brine. The solutionis concentrated on a rotary evaporator and the residue ischromatographed on silica gel (30% ethyl acetate/hexane) to give 3.1 g(12 mmol) of 188 as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 7.40-7.29(m, 5 H), 5.11 (s, 2 H), 4.71 (bd, 1 H), 3.76-3.71 (m, 1 H), 3.53-3.28(m, 3 H), 2.00-1.95 (m, 1 H), 1.90-1.09 (m, 8 H). MS AP⁺ (M+H)⁺=264.3(100%)

Step b: A solution of DMSO (2.52 g, 30 mmol) in CH₂Cl₂ (50 mL) is cooledto −78° C. To this solution is added drop-wise oxalyl chloride (1.81 g,14 mmol) and the resulting solution is stirred for an additional 10 min.Then a solution of alcohol 188 (2.5 g, 9.5 mmol) in CH₂Cl₂ (70 ml) isadded via an addition funnel and stirred for 10 min. Then Et3N (5.0 g,50 mmol) is added and the solution is allowed to warm to roomtemperature. The solution is diluted with water and the organic layerwashed with water, 1 N HCl, and brine. The organic layer is dried overNa₂SO₄, filtered, and concentrated to give 2.5 g (9.5 mmol) of thealdehyde 189 as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 9.59 (d, 3.6Hz, 1 H), 7.38-7.28 (m, 5 H), 5.07 (m, 2 H), 4.69 (m, 1 H), 3.84 (m, 21H), 2.19-2.11 (m,1 H), 2.09-2.01 (m, 1 H), 1.86-1.75 (m, 3 H), 1.54-1.17(m, 4 H).

Step c: A solution of aldehyde 189 (2.0 g, 7.7 mmol),4-(4-fluorophenylmethyl)piperidine hydrochloride (1.8 g, 7.8 mmol) indichloroethane (80 ml) was treated with Na(OAc)₃BH (3.23 g, 15 mmol) and1 ml AcOH and stirred overnight at room temperature. The resultingsolution was diluted with methylene chloride and washed with 1 n NaOH,water, and brine. The organic solvents were removed under vacuum and theresidue chromatographed on silica gel (50% EtOAc/hex—100% EtOAc) to give3.0 g (6.8 mmol) of 190 as an oil.

Step d: A solution of 190 (3.0 g, 6.8 mmol) in MeOH was treated with 1.5g of 10% Pd/C and hydrogenated at 50 psi overnight in a Parr apparatus.The mixture was filtered and the filtrate concentrated on a rotaryevaporator to give 1.8 g (5.9 mmol) of the amine 191 as an oil.

Step e: A solution of amine 191 (200 mg, 0.67 mmol) in THF is treatedwith 3-methoxyphenyl isocyanate (110 mg, 0.75 mmol) and the mixture isstirred for 30 min. The solvent is removed on a rotary evaporator andthe residue is chromatographed on silica gel (50% EtOAc/hex—100% EtOAc)to give 250 mg of urea 192 as a solid. MS esi: (M+H)⁺=454.4 (100%), HRMS(M+H)⁺=454.2875.

Example 415N-(3-acetylphenyl)-N′-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl)methyl]piperidinyl]methyl]cyclohexyl]urea

Step a: To a solution of (R,R) amino alcohol 187 [J. Org. Chem. 1996,61, 5557-5563; J. Am. Chem. Soc. 1996, 118, 5502-5503] (9.5 g, 73.8mmol) in CH₂Cl₂ (200 mL) is added 200 ml of an aqueous solution ofNa₂CO₃ (15 g, 141 mmol). While stirring, benzyl chloroformate (12.6 g,73.8 mmol) is added slowly and the mixture is stirred at roomtemperature for 1 h. The organic layer is separated and washed withwater and brine. The organic solvent is removed on a rotary evaporatorto give a white solid. The solid is recrystallized from hexane to give16.3 g (62 mmol) of the alcohol 188 (Scheme 31a) as a white solid. ¹HNMR (300 MHz, CDCl₃) δ 7.40-7.29 (m, 5 H), 5.11 (s, 2 H), 4.71 (bd, 1H), 3.76-3.71 (m, 1 H), 3.53-3.28 (m, 3 H), 2.00-1.95 (m, 1 H),1.90-1.09 (m, 8 H). MS AP⁺ (M+H)⁺=264.3 (100%)

Step b: A solution of DMSO (36 g, 430 mmol) in CH₂Cl₂ (200 mL) is cooledto −78° C. To this solution is added drop-wise oxalyl chloride (27.41 g,216 mmol) and the resulting solution is stirred for an additional 10min. A solution of alcohol 188 (38 g, 144 mmol) in CH₂Cl₂ (150 ml) isadded via an addition funnel and stirred for 10 min. Then, Et₃N (58 g,570 mmol) is added and the solution is stirred for 20 min and the icebath removed and stirred for an additional 30 min. The solution isdiluted with water and the organic layer separated and washed withwater, 1 N HCl, and brine. The organic layer is dried over Na₂SO₄filtered, and concentrated to give 38 g of aldehyde 189 as a whitesolid. The solid is recrystallized from hexane to give 19.7 grams of afirst crop of aldehyde 189 as white needles. A second crop gave anadditional 11 grams. ¹H NMR (300 MHz, CDCl₃) δ 9.59 (d, 3.6 Hz, 1 H),7.38-7.28 (m, 5 H), 5.07 (m, 2 H), 4.69 (m, 1 H), 3.84 (m, 21 H),2.19-2.11 (m,1 H), 2.09-2.01 (m, 1 H), 1.86-1.75 (m, 3 H), 1.54-1.17 (m,4 H).

Step c: A solution of aldehyde 189 (19.6 g, 75 mmol) and(3S)-3-(4-fluorophenylmethyl)piperidine (14.5 g, 75 mmol) indichloroethane (400 ml) was treated with Na(OAc)₃BH (32 g, 152 mmol) andstirred overnight at room temperature. The resulting solution was pouredslowly into a stirred mixture of ice/water/1 N NaOH and stirred for 20min. The organic layer was separated and washed water, and brine. Thesolution was dried over MgSO₄ and the organic solvent was removed undervacuum and the residue chromatographed on basic alumina (50%EtOAc/hexane) to give 32.1 g (73 mmol) of amine 193 as mixture of (15%)cis and trans isomers. ¹H NMR (300 MHz, CDCl₃) δ 7.79 (bs, 1 H),7.38-7.29 (m, 5 H), 6.95-6.84 (m, 4 H), 5.08 (m, 2 H), 3.71 (m, 1 H, cisisomer), 3.06 (m, 1 H, trans isomer), 2.80 (m, 1 H), 2.55-2.36 (m, 2 H),2.30 (dd, J=9 Hz, J=13 Hz, 1 H, trans isomer), 2.05 (dd, J=2 Hz, J=13Hz, 1 H, trans isomer), 1.81-0.90 (m, 16 H).

Step d: A solution of 193 (32 g, 73 mmol) in MeOH was treated with 8 gof 10% Pd/C and hydrogenated at 50 psi overnight in a Parr apparatus.The mixture was filtered and the filtrate concentrated on a rotaryevaporator to give 20 g (65 mmol) of the amine 194, which was usedwithout further purification.

Step e: A solution of amine 194 (10 g, 32.8 mmol) in THF is treated with3-acetylyphenyl isocyanate (5.3 g, 32.8 mmol) and the mixture is stirredfor 30 min. The solvent is removed on a rotary evaporator and theresidue is chromatographed on silica gel (0.5:4.5:95 NH₄OH/MeOH/CH₂Cl₂)to give 11 g of urea 195 (Example 415) as a solid. Also obtained 2 g ofcis isomer (Example 416a). The urea Example 415 was further purified bya second chromatography on silica gel (40:60:1 EtAc/Hex/TEA) and finalrecrystallization from ether to give crystalline solid. mp 115-117° C.,[α]_(D) ²⁵=+16.8° (CH₃OH, c=0.23 g/dL). ¹H NMR (300 MHz, CDCl₃) δ7.86(m, 1 H), 7.78 (bs, 1 H), 7.68-7.64 (m, 1 H), 7.62-7.59(m, 1 H), 7.38(t, J=8 Hz, 1 H), 6.95-6.90 (m, 2 H), 6.79-6.72 (m, 2 H), 6.25 (s, 1 H),3.21 (dt, J=3 Hz, 11 Hz, 1 H), 3.00-2.97 (m, 1 H), 2.66-2.56 (m, 1 H),2.61 (s, 3 H), 2.44-2.32 (m, 4 H), 2.06 (dd, J=2 Hz, J=13 Hz, 1 H),1.80-0.86 (m, 15 H). MS esi: (M+H)⁺=466.3 (100%). Anal. Calcd forC₂₈H₃₆N₃O₂F: C, 72.23; H, 7.70; N, 9.02. Found: C, 72.33; H, 7.91; N,9.00.

Example 415aN-(3-acetylphenyl)-N′-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl)methyl]piperidinyl]methyl]cyclohexyl]ureaHydrochloride

A solution of example 415 (15 g, 32 mmol) in 300 ml of THF was cooled inan ice bath and treated drop-wise with 36 ml of a 1 M HCl/ethersolution. The resulting solution was stirred for 30 min and concentratedin vacuo. The resulting solid was titurated with ether and the resultingwhite solid dried under high vacuum overnight to give 16 g of thehydrochloride salt. mp 58-60° C. [α]_(D) ²⁵=+20.0° (CH₃OH, c=0.23 g/dL).¹H NMR (400 MHz, DMSO-D₆) δ 9.61 (s, 1 H), 9.15 (s, 1 H), 8.00 (m, 1 H),7.63-7.61 (m, 1 H), 7.51-7.49(m, 1 H), 7.39-7.34 (m, 1 H), 7.22-7.17 (m,2 H), 7.09-7.04 (m, 2 H), 6.86 (d, J=8 Hz, 1 H), 3.47-3.31 (m, 4 H),3.11 (m, 1 H), 2.98-2.82 (m, 2 H), 2.67-2.62 (dd, J=5 Hz, J=13 Hz, 1 H),2.58-2.50 (m, 2 H), 2.52 (s, 3 H), 2.39 (dd, J=8 Hz, J=13 Hz, 1 H),2.16-2.06 (m, 2 H), 1.84-1.556 (m, 7 H), 1.30-1.00 (m, 4 H). Anal. Calcdfor C₂₈H₃₇N₃O₂FCl.H₂O.THF_(0.25): C, 64.73; H 7.68; N, 7.81. Found: C,64.89; H, 7.41; N, 7.81.

Example 415bN-(3-acetylphenyl)-N′-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl)methyl]piperidinyl]methyl]cyclohexyl]ureaBenzenesulfonate

Bezenesulfonic acid monohydrate (1.06 g, 6 mmol) was dried byazeotroping off the water of a benzene solution (twice) and adding thedried acid solution to a solution of example 415 (2.81 g, 6 mmol) intoluene (40 ml). The solvents were removed in vacuo (twice) and theresulting residue recrystallized twice from toluene and dried under highvacuum overnight give 2.77 g of benzenesulfonic acid salt as a whitesolid. mp 157-159° C. [α]_(D) ²⁵=16.9° (CH₃OH, c=0.23 g/dL). Anal. Calcdfor C₃₄H₄₂N₃O₅FS: C, 65.47; H 6.80; N, 6.75; S, 5.14. Found: C, 65.48;H, 6.80; N, 6.70; S, 5.35.

The compounds of Table 3a and Table 3.1 were prepared by proceduresdescribed in Schemes 26-31A, other examples and methods taught herein,and procedures familiar to one skilled in the art.

TABLE 3a

MS Ex # Core R¹⁶ E Z R¹⁴ R³ M + H⁺ 218 p H CH₂ (1) NH H1-(phenylmethyl)- 497 4-piperidinyl] 219 p H CH₂ (1) NH H2,5-difluorophenyl 436 220 p H CH₂ (2) CH₂NH H 2,5-difluorophenyl 450221 p H

(1) NH H 2,5-difluorophenyl 464 222 p H

(1) NH H 2,5-difluorophenyl 466 223 p H C═NH (2) NH H phenyl 413 224 p HCH₂ (2) NH H 1-(phenylmethyl)- 497 4-piperidinyl] 225 p H CH₂ (1) NH H2-(4-fluorophenyl)- 446 ethyl 226 p H CH₂ (1) NH H 3-hydroxypropyl 382227 p H CH₂ (1) NH H 2-(1-piperidinyl)- 435 ethyl 228 p H CH₂ (1) NH H2-(dimethylamino)- 395 ethyl 229 p H CH₂ (1) NH H 4-(phenylmethyl)- 4831-piperazine 230 p H CH₂ (1) NH H 4-(phenylmethyl)- 482 1-piperidine 231p H CH₂ (1) NH H (1,3-benzodioxol- 458 5-ylmethyl) 232 p H CH₂ (1) NH H2,2-(diphenyl)ethyl 504 233 p H CH₂ (1) NH H 4-(4-chlorophenyl)-4- 518hydroxy-1- piperidine 234 p H CH₂ (1) NH H 4-phenyl-4- 484 hydroxy-1-piperidine 235 p H CH₂ (1) NH H 4-phenyl-1- 468 piperidine 236 p H CH₂(1) NH H (1H)-indazol-5-yl 440 237 p H CH₂ (1) NH H (1H)-indazol-6-yl440 238 p H CH₂ (1) NH H phenylmethyl 414 239 p H CH₂ (1) NH H1,3-benzodioxol-5-yl 444 240 p H CH₂ (1) NH

1-(phenylmethyl)- 4-piperidinyl] 541 241 p H CH₂ (1) NH

2-(4-fluorophenyl)ethyl 490 242 p H CH₂ (1) NH

4-((2-phenyl)ethyl)-1- piperazine 541 243 p H CH₂ (1) NH

(1H)-indazol-5-yl 484 244 p H CH₂ (1) NH

(1H)-indazol-6-yl 484 245 p H CH₂ (1) NH

benzothiazol-6-yl 501 246 p H CH₂ (1) NH (4) OH [2-(4-fluorophenyl)- 462ethyl 247 p H CH₂ (1) NH (4) OH 1-(phenylmethyl)- 513 4-piperidinyl] 248p H CH₂ (1) NH

3-phenylpropyl 486 249 p H CH₂ (2) NH H (1H)-indazol-5-yl 440 250 p HCH₂ (2) NH H [2-(4-fluorophenyl)- 446 ethyl 251 p H bond (1) NH H2,5-difluorophenyl 422 252 p H CH₂ (1) NH H Phenyl 400 253 p H CH₂ (1)NH H 4-methoxyphenyl 430 254 p H CH₂ (1) NH H 3-methoxyphenyl 430 255 q4-F CH₂ (2) NH H 3-methoxyphenyl 454 256 q 4-F CH₂ (2) NH H3-acetylphenyl 466 257 r H CH₂ (1) NH H 3-methoxyphenyl 430 258 p H CH₂(2) NH H 3-cyanophenyl 425 259 p H CH₂ (3) NH H 3-cyanophenyl 425 260 pH CH₂ (3) NH H 4-methoxyphenyl 430 261 p H CH₂ (3) NH H 2-phenylethyl428 262 p H CH₂ (1) NH H 3-carboethoxy-phenyl 472 263 p H CH₂ (1) NH H3-cyanophenyl 425 264 p 4-F CH₂ (1) NH H phenyl 418 265 p H CH₂ (1)N-Benzyl H phenyl 490 266 p H CH₂ (1) N-Benzyl H 3-cyanophenyl 515 267 pH CH₂ (1) NH H 2-phenylethyl 428 268 p H CH₂ (1) NH

3-cyanophenyl 469 269 p H CH₂ (1) NH

3-carboethoxy-phenyl 516 270 p H CH₂ (1) NH

4-carboethoxy-phenyl 516 271 p H CH₂ (1) NH (4) OH phenyl 416 272 p HCH₂ (1) NH (4) OH 3-cyanophenyl 441 273 p H CH₂ (1) NH

3-methoxyphenyl 524 274 p H CH₂ (1) NH

Trans-2-phenyl-cyclopropyl 534 275 p H CH₂ (1) NH (3) CO₂Me3-cyanophenyl 483 276 p H CH₂ (1) NH (3) CO₂Me 3-methoxyphenyl 488 277 pH CH₂ (1) NH

3-cyanophenyl 519 278 p H CH₂ (1) NH

3-methoxyphenyl 460 279 p H CH₂ (1) NH

3-cyanophenyl 455 280 p 4-F CH₂ (1) NH (4) CO₂Me 3-cyanophenyl 501 280ap 4-F CH₂ (1) NH (5) CO₂Me 3-cyanophenyl 501 280b p 4-F CH₂ (1) NH (5)CONMe 3-cyanophenyl 500 280c p 4-F CH₂ (1) NH (5) CONH₂ 3-cyanophenyl486 280d p 4-F CH₂ (1) NH (5) CO₂Me 3-(1-hydroxyethyl)- 520 phenyl 280er H CH₂ (1) NH (5) CO₂Me phenyl 458 280f p 4-F CH₂ (1) NH (5) CO₂Hphenyl 462 280g r H CH₂ (1) NH (5) CO₂Me 3-cyanophenyl 483 280h r H CH₂(1) NH (5) CO₂Me 3-methoxyphenyl 488 280i r H CH₂ (1) NH (5) CO₂Me3-acetylphenyl 500 280j p 4-F CH₂ (1) NH (5) CO₂Me 3-acetylphenyl 518HCl(salt) 280k p 4-F CH₂ (1) NH (5) CO₂Me 3-cyanophenyl 501 HCl(salt)281 p 4-F CH₂ (1) NH (4) CO₂Me phenyl 476 281a p 4-F CH₂ (1) NH (5)CO₂Me phenyl 476 281b p 4-F CH₂ (1) NH (5) CONMe phenyl 475 281c p 4-FCH₂ (1) NH (5) CONH₂ phenyl 461 282 p 4-F CH₂ (1) NH (4) CO₂Me3-methoxyphenyl 506 282a p 4-F CH₂ (1) NH (5) CO₂Me 3-methoxyphenyl 506282b p 4-F CH₂ (1) NH (5) CONMe 3-methoxyphenyl 505 282c p 4-F CH₂ (1)NH (5) CO₂Me 3-acetylphenyl 518 282d p 4-F CH₂ (1) NH (5) CONMe3-acetylphenyl 517 282e p 4-F CH₂ (1) NH (5) CONH₂ 3-acetylphenyl 503283 p 4-F CH₂ (1) NH

3-cyanophenyl 473 284 p 4-F CH₂ (1) NH (3-4) 3-cyanophenyl 493 fusedPhenyl 285 p 4-F CH₂ (1) NH (3-4) 3-methoxyphenyl 498 fused Phenyl 286 p4-F CH₂ (1) NH (4) —CONPh 3-cyanophenyl 562 286a p 4-F CH₂ (1) NH (5)—CONPh 3-cyanophenyl 562 286b p 4-F CH₂ (1) NH (5) —CONPh 3-acetylphenyl579 287 p 4-F CH₂ (1) NH

3-methoxyphenyl 478 288 p 4-F CH₂ (1) NH (4) CONMe 3-cyanophenyl 500288a p 4-F CH₂ (1) NH (4) CONMe 3-cyanophenyl 500 HCl(salt) 288b p 4-FCH₂ (1) NH (5) CONMe 3-acetylphenyl 517 HCl(salt) 288c p 4-F CH₂ (1) NH(5) 3-acetylphenyl 574 CON(CH₂)₂NMe₂ 288d p 4-F CH₂ (1) NH (5)3-acetylphenyl 557 CON(CH₂)₂NMe₂ 288e p 4-F CH₂ (1) NH (5)3-acetylphenyl 453 CONC₃H₅ 288f p 4-F CH₂ (1) NH (5) 3-acetylphenyl 531CONC₃H₅ 288g p 4-F CH₂ (1) NH (5) 3-methoxyphenyl 519 CONMe₂ 288h p 4-FCH₂ (1) NH (5) 3-acetylphenyl 531 CONMe₂ 288i p 4-F CH₂ (1) NH (5)3-acetylphenyl 580 CON(2-pyridinyl) 288j p 4-F CH₂ (1) NH (5)3-methoxyphenyl 568 CONMe₂ 289 p H CH₂ (1) CH₂NH H 2,5-difluorophenyl450 290 p H CH₂ (1) CH₂NH H 3-cyanophenyl 439 291 p H CH₂ (1) CH₂NH H3-carboethoxy-phenyl 486 292 p H CH₂ (1) CH₂NH H 3-methoxyphenyl 444 293p H CH₂ (1) CH₂NH H 4-methoxyphenyl 444 294 p H

(1) NH H 3-methoxyphenyl 460 295 r H

(1) NH H 3-methoxyphenyl 460 296 p H

(1) NH H 3-cyanophenyl 455 297 p H

(1) NH H 3-carboethoxy-phenyl 502 298 p H

(1) NH H phenyl 430 299 p 4-F CH₂ (1) NH

phenyl 448 300 p H

(1) NH H phenyl 443 301 p H

(2) NH H phenyl 428 302 p H

(2) NH H phenyl 430 303 p 4-F

(1) NH H phenyl 448 304 p 4-F

(1) NH H 3-methoxyphenyl 478 305 p 4-F

(1) NH H 3-cyanophenyl 473 306 p H

(1) NH

3-cyanophenyl 499 307 p H CH₂—CH₂ (1) NH H 3-cyanophenyl 439 308 p 4-FCH₂—CH₂ (1) NH H 3-cyanophenyl 457 309 p H CH₂—CH₂ (1) NH H3-methoxyphenyl 444 310 p 4-F CH₂—CH₂ (1) NH H 3-methoxyphenyl 462 311 rH CH₂—CH₂ (1) NH H 3-methoxyphenyl 444 312 p 4-F CH₂—CH₂ (1) NH H3-acetylphenyl 474 313 p 4-F CH₂—CH₂ (1) NH H 4-fluorophenyl 450 314 p4-F CH₂—CH₂ (1) NH H 1-adamantyl 490 315 s H CH₂ (1) NH

3-cyanophenyl 483(M+) 316 s H CH₂ (1) NH (4) OH 3-cyanophenyl 455(M+)317 s H CH₂ (1) NH (4) O-(2-THP) 3-cyanophenyl 539(M+)

TABLE 3.1

Stereo- Salt MS Ex # Core R¹⁶ chemistry Form R³ M + H⁺ 400 a H 1,2 trans— 3-methoxylphenyl 436 racemic 401 a 4-F 1,2 trans — 3-methoxylphenyl454 racemic 402 a H 1,2 cis — 3-methoxylphenyl 436 racemic 403 a 4-F 1,2trans — 3-cyanophenyl 449 racemic 403a a 4-F 1,2 trans — 3-acetylphenyl466 racemic 403b a 4-F 1,2 trans — 3-nitrophenyl 469 racemic 403c a 4-F1,2 trans — 4-nitrophenyl 469 racemic 403d a 4-F 1,2 trans — 4-pyridinyl425 racemic 403e a 4-F 1,2 trans HCl 3-acetylphenyl 466 racemic 403f a4-F 1,2 trans — (1H)-indazol-5-yl 464 racemic 404 a 4-F 1S, 2R —3-acetylphenyl 466 405 a 4-F 1S, 2R — 3-cyanophenyl 449 406 a 4-F 1S, 2R— 3-methoxylphenyl 454 407 a 4-F 1S, 2R — phenyl 424 408 a 4-F 1R, 2S —3-acetylphenyl 466 409 a 4-F 1R, 2S — 3-cyanophenyl 449 410 a 4-F 1R, 2S— 3-methoxyphenyl 454 411 a 4-F 1R, 2S — phenyl 424 412 a 4-F 1R, 2S —phenylmethyl 438 413 a 4-F 1R, 2S — (1H)-indazol-5-yl 464 414 a 4-F 1R,2S — (1H)-indol-5-yl 463 414a b H 1,2 trans — 3-methoxyphenyl 464 (3RS)racemic 414b b H 1,2 trans — 3-cyanophenyl 431 (3RS) racemic 414c b H1,2 trans — 3-acetylphenyl 448 (3RS) racemic 414d b 4-F 1,2 trans —3-acetylphenyl 466 (3RS) racemic 414e b 4-F 1,2 trans — 3-cyanophenyl449 (3RS) racemic 414f b 4-F 1,2 trans — 3-methoxyphenyl 454 (3RS)racemic 414g b 4-F 1,2 trans — 3-nitrophenyl 469 (3RS) racemic 415 b 4-F1R, 2S, 3S — 3-acetylphenyl 466 415a b 4-F 1R, 2S, 3S HCl 3-acetylphenyl466 415b b 4-F 1R, 2S, 3S Besyl 3-acetylphenyl 466 416 b 4-F 1R, 2S, 3R— 3-acetylphenyl 466 416a b 4-F 1R, 2R, 3S — 3-acetylphenyl 466 416b b4-F 1R, 2S, 3R HCl 3-acetylphenyl 466 417 b 4-F 1R, 2S, 3S —3-cyanophenyl 449 418 b 4-F 1R, 2S, 3R — 3-cyanophenyl 449 419 b 4-F 1R,2S, 3S — 3-methoxylphenyl 454 420 b 4-F 1R, 2S, 3R — 3-methoxylphenyl454 421 b 4-F 1R, 2S, 3S — 4-fluorophenyl 442 422 b 4-F 1R, 2S, 3R —4-fluorophenyl 442 423 b 4-F 1R, 2S, 3S — phenyl 424 424 b 4-F 1R, 2S,3S — (1H)-indazol-5-yl 464 425 b 4-F 1R, 2S, 3S — (1H)-indazol-6-yl 464426 b 4-F 1R, 2S, 3S — benzthiazol-6-yl 481 427 b 4-F 1R, 2S, 3S —(1H)-indol-5-yl 463 428 b 4-F 1R, 2S, 3S — (1H)-indol-6-yl 463 429 b 4-F1R, 2S, 3S — (1H)-2,3- 491 dimethylindol-5-yl 430 b 4-F 1R, 2S, 3S —benzimidazol-5-yl 464 431 b 4-F 1R, 2S, 3S — indolin-5-yl 465 432 b 4-F1R, 2S, 3S — 3-cyano-4-fluorophenyl 467 433 b 4-F 1R, 2S, 3S —3-acetyl-4- 484 fluorophenyl 434 b 4-F 1R, 2S, 3S — 3,5-diacetylphenyl508 435 b 4-F 1R, 2S, 3S — 3-(1-hydroxyethyl)- 468 phenyl 436 b 4-F 1R,2S, 3S — 4-methyl-thiazol-2-yl 445 437 b 4-F 1R, 2S, 3S —4-methyl-5-acetyl- 487 thiazol-2-yl 438 b 4-F 1R, 2S, 3S —1,3,4-thiadiazol-2-yl 432 439 b 4-F 1R, 2S, 3S — 4-chlorol-benzthiazol-515 2-yl 440 b 4-F 1R, 2S, 3S — thiazol-2-yl 431 441 b 4-F 1R, 2S, 3S —5-methyl-isoxazol-3-yl 429 442 b 4-F 1R, 2S, 3S — 1-methyl-pyrazol-3-yl428 443 b 4-F 1R, 2S, 3S — 4-(1,2,4-triazol-1- 491 yl)phenyl 443a b 4-F1R, 2R, 3S — 4-(1,2,4-triazol-1- 491 yl)phenyl 444 b 4-F 1R, 2S, 3S —(1H)-3-chloro-indazol- 499 5-yl 445 b 4-F 1R, 2S, 3S — 4-fluorophenyl492 446 b 4-F 1R, 2S, 3S — 4-chlorophenyl 458 447 b 4-F 1R, 2S, 3S —4-bromophenyl 502 448 b 4-F 1R, 2S, 3S — 3-bromophenyl 502 449 b 4-F 1R,2S, 3S — 3-fluorophenyl 442 450 b 4-F 1R, 2S, 3S — 3,4-difluorophenyl460 451 b 4-F 1R, 2S, 3S — 3-chloro-4- 476 fluorophenyl 452 b 4-F 1R,2S, 3S — 3,5-dichlorophenyl 492 453 c 4-F 1R, 2S, 3S — 3-acetylphenyl452 454 c 4-F 1R, 2S, 3R — 3-acetylphenyl 452 455 c 4-F 1R, 2R, 3S —3-acetylphenyl 452 456 c 4-F 1R, 2S, 3S — 3-cyanophenyl 435 457 c 4-F1R, 2S, 3R — 3-cyanophenyl 435 458 c 4-F 1R, 2R, 3S — 3-cyanophenyl 435458a c 4-F 1R, 2R, 3R — 3-cyanophenyl 435 459 c 4-F 1R, 2S, 3S — phenyl410 460 c 4-F 1R, 2S, 3R — phenyl 410 461 c 4-F 1R, 2R, 3S — phenyl 410462 b 4-F 1R, 2S, 3S — (1H)-5-amino-indazol- 464 1-yl 463 b 4-F 1R, 2S,3S — 3-chlorophenyl 458 464 b 4-F 1R, 2S, 3S — 3-fluoro-4- 456methylphenyl 465 b 4-F 1R, 2S, 3S — 3-cyano-4-(1- 515 pyrazolyl)phenyl466 b 4-F 1R, 2S, 3S — 2-methylphenyl 454 467 b 4-F 1R, 2S, 3S —2-methylphenyl 438 468 b 4-F 1R, 2S, 3S — 2,4-dimethylphenyl 452 469 b4-F 1R,,2S, 3S — 2,4-dimethoxyphenyl 484 470 b 4-F 1R, 2S, 3S —2,5-dimethoxyphenyl 484 471 b 4-F 1R, 2S, 3S — 2-methoxy-5- 468methylphenyl 472 b 4-F 1R, 2S, 3S — 2-methyl-5- 456 fluorophenyl 473 b4-F 1R, 2S, 3S — 3,5-bis((1H)-1- 588 methyltetrazol-5- yl)phenyl 474 b4-F 1R, 2S, 3S — (3-((1H)-1- 506 methyltetrazol-5- yl)phenyl 475 b 4-F1R, 2S, 3S — (4-(carboethoxymethyl) 517 thiazol-2-yl 476 b 4-F 1R, 2S,3S — 5-bromothiazol-2-yl 509 477 b 4-F 1R, 2S, 3S —4,5-di(4-fluorophenyl) 619 thiazol-2-yl 478 b 4-F 1R, 2S, 3S —2-fluorophenyl 442 479 b 4-F 1R, 2S, 3S — 2-chlorophenyl 458 480 b 4-F1R, 2S, 3S CF₃CO₂H indanon-6-yl 478 481 b 4-F 1R, 2S, 3S CF₃CO₂Hindanon-4-yl 478 482 b 4-F 1R, 2S, 3S CF₃CO₂H 4-(isopropyl)phenyl 466483 b 4-F 1R, 2S, 3S CF₃CO₂H 3-nitro-4-methylphenyl 483 484 b 4-F 1R,2S, 3S CF₃CO₂H trans-2- 464 phenylcycloprop-1-yl 485 b 4-F 1R, 2S, 3SCF₃CO₂H 2,4-difluorophenyl 460 486 b 4-F 1R, 2S, 3S CF₃CO₂H2,5-difluorophenyl 460 487 b 4-F 1R, 2S, 3S CF₃CO₂H 2,4-dichlorophenyl492 488 b 4-F 1R, 2S, 3S CF₃CO₂H 2,5-dichlorophenyl 492 489 b 4-F 1R,2S, 3S CF₃CO₂H 2-methoxyphenyl 454 490 b 4-F 1R, 2S, 3S CF₃CO₂H2,4-dimethoxy-phenyl 484 491 b 4-F 1R, 2S, 3S CF₃CO₂H2,5-dimethoxyphenyl 484 492 b 4-F 1R, 2S, 3S CF₃CO₂H 2- 492trifluoromethylyphenyl 493 b 4-F 1R, 2S, 3S CF₃CO₂H 2-methylphenyl 438494 b 4-F 1R, 2S, 3S CF₃CO₂H 3-trifluoromethyly- 492 phenyl 495 b 4-F1R, 2S, 3S CF₃CO₂H 3-methylphenyl 438 496 b 4-F 1R, 2S, 3S CF₃CO₂H4-methoxyphenyl 454 497 b 4-F 1R, 2S, 3S CF₃CO₂H 4-carboethoxy-phenyl496 498 b 4-F 1R, 2S, 3S CF₃CO₂H 4-trifluoromethyly- 492 phenyl 499 b4-F 1R, 2S, 3S CF₃CO₂H 4-methylphenyl 438 500 b 4-F 1R, 2S, 3S CF₃CO₂H2-fluorophenyl 442 501 b 4-F 1R, 2S, 3S CF₃CO₂H 2-chlorophenyl 458 502 b4-F 1R, 2S, 3S CF₃CO₂H 2-nitrophenyl 469 503 b 4-F 1R, 2S, 3S CF₃CO₂H2,4-dichlorophenyl 563 504 b 4-F 1R, 2S, 3S CF₃CO₂H 3-nitrophenyl 469505 b 4-F 1R, 2S, 3S CF₃CO₂H 3,5-di 560 (trifluoromethyly)- phenyl 506 b4-F 1R, 2S, 3S CF₃CO₂H 2,4-dimethylyphenyl 452 507 b 4-F 1R, 2S, 3SCF₃CO₂H 2,4-dimethoxy-5- 518 chlorophenyl 508 b 4-F 1R, 2S, 3S CF₃CO₂H3,4,5-trimethoxyphenyl 514 509 b 4-F 1R, 2S, 3S CF₃CO₂H3,5-dimethylphenyl 452 510 b 4-F 1R, 2S, 3S CF₃CO₂H 3-trifluoromethyl-4-526 chlorophenyl 511 b 4-F 1R, 2S, 3S CF₃CO₂H 4-phenoxyphenyl 516 512 b4-F 1R, 2S, 3S CF₃CO₂H 4-ethoxyphenyl 468 513 b 4-F 1R, 2S, 3S CF₃CO₂H4-thiomethylphenyl 470 514 b 4-F 1R, 2S, 3S CF₃CO₂H 2-naphthyl 474 515 b4-F 1R, 2S, 3S CF₃CO₂H 4-acetylphenyl 466 516 b 4-F 1R, 2S, 3S CF₃CO₂H2,6-dichloro-pyridin-4-yl 493 517 b 4-F 1R, 2S, 3S CF₃CO₂H 5-indan-4-yl464 518 b 4-F 1R, 2S, 3S CF₃CO₂H 4-chloronaphth-1-yl 508 519 b 4-F 1R,2S, 3S CF₃CO₂H 3-fluoro-4- 472 methoxyphenyl 520 b 4-F 1R, 2S, 3SCF₃CO₂H 4-(methylsulfonyl)- 502 phenyl) 521 b 4-F 1R, 2S, 3S CF₃CO₂H3-(methylsulfonyl)- 502 phenyl 522 b 4-F 1R, 2S, 3S CF₃CO₂H2-((1H)-pyrrol-1- 489 yl)phenyl 523 b 4-F 1R, 2S, 3S CF₃CO₂H1,3-benzodioxol-5-yl 468 524 b 4-F 1R, 2S, 3S CF₃CO₂H1-acetylindolin-6-yl 507 525 b 4-F 1R, 2S, 3S CF₃CO₂H 4-(6- 571methylbenzothiazol-2- yl)phenyl 526 b 4-F 1R, 2S, 3S CF₃CO₂H 4-((2,2-523 dimethylpropanoyl) amino)phenyl 527 b 4-F 1R, 2S, 3S CF₃CO₂H4-(1-methyltetrazol-5- 506 yl)phenyl 528 b 4-F 1R, 2S, 3S CF₃CO₂H4-(1-morpholino)phenyl 509 529 b 4-F 1R, 2S, 3S CF₃CO₂H quinolin-8-yl475 530 b 4-F 1R, 2S, 3S CF₃CO₂H 3-hydroxyphenyl 440 531 b 4-F 1R, 2S,3S CF₃CO₂H 4-(acetylamino)-phenyl 481 532 b 4-F 1R, 2S, 3S CF₃CO₂H4-hydroxyphenyl 440 533 b 4-F 1R, 2S, 3S CF₃CO₂H 3-hydroxy-4- 470methoxyphenyl 534 b 4-F 1R, 2S, 3S CF₃CO₂H 3-(acetylamino)-phenyl 481535 b 4-F 1R, 2S, 3S CF₃CO₂H 4-fluoro-3- 456 methylphenyl 536 b 4-F 1R,2S, 3S CF₃CO₂H 3-methoxy-4- 468 methylphenyl 537 b 4-F 1R, 2S, 3SCF₃CO₂H 4-chloro-3- 472 methylphenyl 538 b 4-F 1R, 2S, 3S CF₃CO₂H 4-(N-481 methylcarboxamide)phenyl 539 b 4-F 1R, 2S, 3S CF₃CO₂H 1-adamantyl482 540 b 4-F 1R, 2S, 3S CF₃CO₂H quinolin-5-yl 475 541 b 4-F 1R, 2S, 3SCF₃CO₂H quinolin-6-yl 475 542 b 4-F 1R, 2S, 3S CF₃CO₂H1,4-benzodioxan-6-yl 482 543 b 4-F 1R, 2S, 3S CF₃CO₂H isoquinolin-5-yl475 544 b 4-F 1R, 2S, 3S CF₃CO₂H 4-(sulfonamide)-phenyl 503 545 b 4-F1R, 2S, 3S CF₃CO₂H benzotriazol-5-yl 465 546 b 4-F 1R, 2S, 3S CF₃CO₂H2-hydroxy-4- 454 methylphenyl 547 b 4-F 1R, 2s,3s CF₃CO₂H 3-hydroxy-4-454 methylphenyl 548 b 4-F 1R, 2S, 3S CF₃CO₂H 2-methyl-benzothiazol- 4955-yl 549 b 4-F 1R, 2S, 3S CF₃CO₂H (4-methoxylphenyl)- 468 methyl 550 b4-F 1R, 2S, 3S CF₃CO₂H (4-fluorophenyl)- 456 methyl 551 b 4-F 1R, 2s, 3SCF₃CO₂H (4-methylphenyl)- 452 methyl 552 b 4-F 1R, 2S, 3S CF₃CO₂H(1R)-1-(phenyl)ethyl 452 553 b 4-F 1R, 2S, 3S CF₃CO₂H1-acetylindolin-5-yl 507 554 b 4-F 1R, 2S, 3S CF₃CO₂H 5,6,7,8- 478tetrahydronaphth-1-yl 555 b 4-F 1R, 2S, 3S CF₃CO₂H 3-acetyl-4- 482hydroxyphenyl 556 b 4-F 1R, 2S, 3S CF₃CO₂H 4-(piperidin-1- 507 yl)phenyl557 b 4-F 1R, 2S, 3S CF₃CO₂H cyclohexyl 430 558 b 4-F 1R, 2S, 3S CF₃CO₂H2-methoxyphenyl 468 559 b 4-F 1R, 2S, 3S CF₃CO₂H 2,6-dimethylphenyl 452560 b 4-F 1R, 2S, 3S CF₃CO₂H 2-ethylphenyl 452 561 b 4-F 1R, 2S, 3SCF₃CO₂H 2,4,6-trimethylphenyl 466 562 b 4-F 1R, 2S, 3S CF₃CO₂H2,5-dimethoxyphenyl 484 563 b 4-F 1R, 2S, 3S CF₃CO₂H t-butyl 404 564 b4-F 1R, 2S, 3S CF₃CO₂H i-propyl 390 565 b 4-F 1R, 2S, 3s CF₃CO₂HEthoxycarbonyl-methyl) 434 566 b 4-F 1R, 2S, 3S CF₃CO₂H2-trifluoromethoxy- 508 phenyl 567 b 4-F 1R, 2S, 3S CF₃CO₂H (1R,S)-1-462 (methoxycarbonyl)-2- methyl-propyl 568 b 4-F 1R, 2S, 3S CF₃CO₂H[(1S)-1- 510 (methoxycarbonyl)-2- phenylethyl 569 b 4-F 1R, 2S, 3SCF₃CO₂H 2,4,4-trimethyl-2- 460 pentyl 570 b 4-F 1R, 2S, 3S CF₃CO₂H2-phenylethyl 452 571 b 4-F 1R, 2S, 3S CF₃CO₂H 3-acetylphenyl 466 572 b4-F 1R, 2S, 3S CF₃CO₂H 2-carbomethoxy-phenyl 482 573 b 4-F 1R, 2S, 3SCF₃CO₂H (1S)-1-(phenyl)ethyl 452 574 b 4-F 1R, 2S, 3S CF₃CO₂H4-(phenyl)phenyl 500 575 b 4-F 1R, 2S, 3S CF₃CO₂H 1-naphthyl 474 576 b4-F 1R, 2S, 3S CF₃CO₂H 2-(phenyl)phenyl 500 577 b 4-F 1R, 2S, 3S CF₃CO₂HPhenylmethoxy 454 578 b 4-F 1R, 2S, 3S CF₃CO₂H 3,4-dimethoxyphenyl 484579 b 4-F 1R, 2S, 3S CF₃CO₂H (3H)-2- 520 ethylquinazolin-4-on-3-yl 580 b4-F 1R, 2S, 3S CF₃CO₂H 3-pyridinyl 425 581 b 4-F 1R, 2S, 3S CF₃CO₂H6-methoxy-3-pyridinyl 455 582 b 4-F 1R, 2S, 3S CF₃CO₂H2-methylquinolin-8-yl 489 583 b 4-F 1R, 2S, 3S CF₃CO₂H2-methylnaphth-1-yl 488 584 b 4-F 1R, 2S, 3S CF₃CO₂H 4-((1H)-1-propyl-534 tetrazol-5-yl)phenyl 585 b 4-F 1R, 2S, 3S CF₃CO₂H 3-aminophenyl 439586 b 4-F 1R, 2S, 3S — 3-(acetylamino)-phenyl 481 587 b 4-F 1R, 2S, 3SCF₃CO₂H 3-(N-methylcarbamoyl)- 481 phenyl 588 b 4-F 1R, 2S, 3S CF₃CO₂H2-nitro-4- 499 methoxyphenyl 589 b 4-F 1R, 2S, 3S CF₃CO₂H8-hydroxyquinolin-5-yl 491 590 b 4-F 1R, 2S, 3S CF₃CO₂H3-methylpyridin-2-yl 439 591 b 4-F 1R, 2S, 3S CF₃CO₂H isoquinolin-1-yl475

Example 318

Part A: Preparation of 1-t-butyloxycarbonyl-4-benzylpiperidine

4-benzylpiperidine (10.0 g, 57.1 mmol, 1.0 eq.) was dissolved in 100 mLof THF under N₂ and subsequently cooled to 0° C. Di-tert-butyldicarbonate (11.21 g, 51.3 mmol, 0.9 eq.) dissolved in 50 mL of THF, wasadded dropwise. Gas evolution was observed. Once gas evolution ceased,the ice bath was removed. After 20 hours, the THF was removed in vacuothen the residue was dissolved in EtOAc and rinsed 3× with 1N citricacid, 1× with brine. The organic was dried over magnesium sulfate andstripped to yield 15.4 g of colorless oil as product. Yield=97.9%. NMR(300 MHz, CDCl₃)δ 7.35-7.17 (m,3H); 7.14 (d, 2H, J=7 Hz); 4.20-3.90 (m,2H); 2.75-2.55 (m, 2H); 2.54 (d, 2H, J=7 Hz); 1.70-1.50 (m, 3H); 1.46(s, 9H); 1.20-1.00 (m, 2H).

Part B: Preparation of erythro-andthreo-cis-4-benzyl-1-t-butoxycarbonyl-•-ethylpiperidinemethanol

1-t-butyloxycarbonyl-4-benzylpiperidine (5.0 g, 18.2 mmol, 1.0 eq.) wasdissolved in Et₂O at 25° C. under N₂ and cooled to −78° C.N,N,N′,N′-Tetramethylethylenediamine (TMEDA) (3.29 mL, 21.8 mmol, 1.2eq.) was added followed by the dropwise addition of sec-butyllithium(16.76 mL, 21.8 mmol, 1.2 eq.). The reaction was allowed to warm andstir at −30° C. for 30 minutes then again cooled to −78° C. Once cool,propionaldehyde (1.31 mL, 20.0 mmol, 1.1 eq.) was added neat. Thereaction was allowed warmed to warm to −30° C. then immediately quenchedwith 10 mL of water and the organic layer was separated. The aqueouslayer was extracted 2× more with Et₂O. The organic layers were combined,dried over magnesium sulfate and the solvent removed in vacuo to yield acolorless oil which was purified by flash chromatography in 4:1 to 1:1hexane/EtOAc. Obtained 0.68 g of a colorless oil as isomer A,yield=11.2% and 0.91 g of a colorless oil as isomer B, yield=15.0%.

Isomer A NMR (300 MHz, CDCl₃)δ7.40-7.25 (m, 2H); 7.21 (d, 1H, J=7 Hz);7.16 (d, 2H, J=7 Hz); 3.60-3.30 (m, 2H); 2.56 (d, 2H J=7 Hz); 1.90-1.00(m, 7H); 1.46 (s, 9H); 1.00-0.70 (m, 5H).

Isomer B NMR (300 MHz, CDCl₃)δ7.30-7.23 (m, 2H); 7.20 (d, 1H, J=7 Hz);7.14 (d, 2H, J=7 Hz.); 3.60-3.20 (m, 2H); 2.60-2.40 (m, 2H); 1.90-1.00(m, 9H); 1.44 (s, 9H); 0.96 (t, 3H, J=7 Hz).

Part C: Structure determination of Isomer B via cyclization to4α,6α,7α-4-benzyl-7-ethyl-8-oxa-1-azabicyclo[4.3.0]nonane-9-one

Isomer B (60 mg, 0.18 mmol, 1 eq.) was dissolved in DMF at 25° C. underN₂ then NaH (7.9 mg, 0.198 mmol, 1 eq.) was added. After 20 hours, 2 mLof water was added followed by EtOAc. The layers were separated. Theaqueous layer was extracted 2× more with EtOAc. The organic layers werecombined, dried over magnesium sulfate, and the solvent removed in vacuoto yield an oil which was purified over silica gel in 9:1 to 1:1hexane/EtOAc. Obtained 30 mg. Yield=64%. Product structure confirmed byN.O.E. NMR (300 MHz, CDCl₃) δ 7.40-7.20 (m, 3H); 7.16 (d, 2H, J=7 Hz);4.45-4.25 (m, 1H); 4.00-3.80 (m, 1H); 3.65-3.45 (m, 1H); 2.95-2.70 (m,1H); 2.65-2.45 (m, 2H); 1.85-1.40 (m, 4H); 1.40-1.00 (m, 6H).

Part D: Preparation of erythro-cis-4-benzyl-α-ethylpiperidinemethanol

Erythro-cis-4-benzyl-1-t-butoxycarbonyl-•-ethylpiperidinemethanol(isomer B from part B) (815 mg, 2.44 mmol, 1 eq.) was dissolved in 8 mLof ethanol at 25° C. under N₂. NaOH (391 mg, 9.78 mmol, 4 eq.) was addedand the mixture refluxed for 4 hours. The solvent was removed in vacuoto yield an oil. Water was added followed by EtOAc. The layers wereseparated. The aqueous layer was extracted 2× more with EtOAc. Theorganic layers were combined dried over magnesium sulfate, and thesolvent removed in vacuo to yield 390 mg of an oil. Yield=68%. NMR (300MHz, CDCl₃) • 7.35-7.20 (m, 2H); 7.23-7.00 (m, 3H); 3.75-3.65 (m, 1H);3.20-3.00 (m, 1H); 2.90-2.40 (m, 4H); 1.70-1.50 (m, 2H); 1.50-1.30 (m,1H); 1.20-0.80 (m, 5H).

Part E: Preparation oferythro-cis-4-benzyl-α-ethyl-1-(3-N-phthalimido-n-prop-1-yl)piperidinemethanol

Erythro-cis-4-benzyl-α-ethylpiperidinemethanol (195 mg, 0.84 mmol, 1eq.), N-(3-bromopropyl)phthalimide (224 mg, 0.84 mmol, 1 eq.), potassiumiodide (139 mg, 0.84 mmol, 1 eq.), and potassium carbonate (231 mg, 0.84mmol, 1 eq.) were refluxed in 10 mL of 2-butanone for 3 hours. Thereaction was worked up by filtering off the inorganic solids. Thefiltrate solvent was removed in vacuo to yield an oil. Purified by flashchromatography in 100% EtOAc then 4:1 chloroform/MeOH. Obtained 200 mg.Yield=57%. NMR (300 MHz, CDCl₃) δ 7.95-7.80 (m, 2H); 7.80-7.65 (m, 2H);7.35-7.00 (m, 5H); 3.90-3.60 (m, 3H); 3.20-2.90 (m, 2H); 2.65-2.30 (m,3H); 2.20-2.00 (m, 2H); 2.00-1.75 (m, 2H); 1.70-1.40 (m, 4H); 1.35-0.90(m, 3H); 0.96 (t, 3H, J=7 Hz).

Part F: Preparation oferythro-cis-1-(3-amino-n-prop-1-yl)-4-benzyl-α-ethylpiperidinemethanol

Erythro-cis-4-benzyl-α-ethyl-1-(3-N-phthalimido-n-prop-1-yl)piperidinemethanol(200mg, 0.48 mmol, 1 eq.) was dissolved in 5 mL of ethanol at 25° C. underN₂. Anhydrous hydrazine (0.03 mL, 0.95 mmol, 2 eq.) was added and thereaction refluxed for 3 hours during which time a white precipitate(phthalhydrazide) formed. Once cool, The solids were filtered. Thefiltrate solvent was removed in vacuo to yield an oil which was stirredin Et₂O. The triturated solids were filtered and the filtrate solventwas removed in vacuo to yield 120 mg of an oil. Yield=87%. NMR (300 MHz,CDCl₃) δ 7.27 (t, 2H, J=7 Hz); 7.17 (d, 1H, J=7 Hz); 7.13 (d, 2H, J=7Hz); 3.70-3.30 (m, 2H); 3.20-3.00 (m, 2H); 3.00-2.70 (m, 2H); 2.70-2.40(m, 2H); 2.30-2.10 (m, 1H); 2.10-1.90 (m, 2H); 1.90-1.40 (m, 5H);1.40-1.00 (m, 3H); 0.96 (t, 3H, J=7 Hz).

Part G: preparation oferythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl]-4-benzyl-α-ethylpiperidinemethanolanderythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl]-2-[1-(3-acetylphenylaminocarbonyloxy)-n-prop-1-yl)-4-benzylpiperidine

Erythro-cis-1-(3-amino-n-prop-1-yl)-4-benzyl-α-ethylpiperidinemethanol(120 mg, 0.41 mmol, 1 eq.) was dissolved in 5 mL of THF at 25° C. underN₂ then 3-acetylphenyl isocyanate added neat. After 1 hour the solventwas removed in vacuo to yield an oil. Purified by flash chromatographyin 100% EtOAc to 4:1 chloroform/MeOH. Isolated mono-addition product(product A) along with an additional bis-addition product (product B).Prouct A yielded 81 mg of an oil. Yield=43%. Product B yielded 43 mg ofan oil.

Product A NMR (300 MHz, CDCl₃) δ 7.86 (bs, 1H); 7.73 (d, 1H, J=7 Hz);7.60 (s, 1H); 7.56 (d, 1H, J=7 Hz); 7.40-7.15 (m, 4H); 7.12 (d, 2H, J=7Hz); 6.30-6.05 (m, 1H); 4.00-3.80 (m, 1H); 3.50-3.30 (m, 1H); 3.30-2.90(m, 5H); 2.60-2.40 (m, 2H); 2.57 (s, 3H); 2.30-2.10 (m, 1H); 2.10-1.90(m, 2H); 1.80-1.40 (m, 5H); 1.30-1.05 (m, 2H); 0.94 (t, 3H, J=7 Hz).

Product B NMR (300Mhz, CDCl₃) δ 10.80-10.60 (m, 1H); 8.20-8.00 (m,1H);7.91 (bs, 1H); 7.80-7.18 (m, 9H); 7.11 (d, 2H, J=7 Hz); 6.20-6.00 (m,1H); 5.20-5.00 (m, 1H); 3.50-3.00 (m, 4H); 2.57 (s, 3H); 2.56 (s, 3H);2.55-2.00 (m, 5H); 2.00-1.00 (m, 10H); 1.00-0.80 (m, 3H)

Product A was seperated into its enantiomers employing a Daicel ChiralPack AD column, eluting with 0.1% diethylamine in methanol. (−)-isomer[α]_(D) ²⁵ (c=0.300 g/dL, MeOH)=−14.9°. (+)-isomer [α]_(D) ²⁵ (c=0.290g/dL, MeOH=+20.2°.

The following compounds can be synthesized by the methods discussedpreviously.

TABLE 3b

Cores R1 R2 R2a, R2b R3 M + 1 319 a, b H CH3 — 3-COCH3 438 320 a, b HCH3 — 4-NO2 441 321 a, b H CH3CH2 — 3-COCH3 452 322 c H — CH3, CH33-COCH3 452 323 a, b H CH3CH2CH2 — 3-COCH3 466 324 a, b H (CH3)2CH —3-COCH3 466 325 a, b H CH3CH2CH2CH2 — 3-COCH3 480 326 a, b H (CH3)2CHCH2— 3-COCH3 480 327 d, e H CH3CH2 — 3-COCH3 613 328 d, e H CH3CH2CH2 —3-COCH3 627 329 d, e H (CH3)2CH — 3-COCH3 627 330 d, e H CH3CH2CH2CH2 —3-COCH3 641 331 d, e H (CH3)2CHCH2 — 3-COCH3 641

Example 332

Part A Preparation of N-cyano-N′-3-methoxyphenylcarbamimidic acid,phenyl ester

m-Anisidine (4.56 mL, 4.06 mmol, 1 eq.), and diphenylcyanocarbonimidate(967 mg, 4.06 mmol, 1 eq.) were mixed and refluxed in acetonitrile underN2 for 1 hour. Solids precipitated. The reaction was worked up byfiltering off the solids. Obtained 580 mg as product.

M.P.=170.0-171.0° C. NMR (300 MHz, DMSO-d₆) 67 8.70-8.50 (m, 1H); 7.43(t, 2H, J=7 Hz); 7.40-7.20 (m, 2H); 7.14 (d, 2H, J=7 Hz); 7.00-6.80 (m,2H); 6.80-6.70 (m, 1H); 3.80 (s, 3H).

Part B Preparation ofN″-cyano-N′-(3-[4-(4-fluorobenzyl)piperidinel]propyl-N-(3-methoxyphenyl)quanidine

3-(4-(4-fluorophenylmethyl)piperidin-1-yl)propylamine, (synthesized in asimilar fashion to the previously described des-fluoro compound) (53 mg,0.20 mmol, 1 eq.) and the product from Part A (50 mg, 0.20 mmol, 1 eq.)were mixed and refluxed in 2-propanol under N₂ for 1 hour. The reactionwas stripped and the residue then purified over silica gel in 100% ethylacetate followed by 8:2 chloroform/methanol. Obtained 55 mg of off-whitesolids as product. NMR (300 MHz, CDCl₃) δ 7.33 (t, 1H, J=7 Hz);7.10-6.90 (m, 4H); 6.90-6.80 (m, 3H); 3.83 (s, 3H); 3.50-3.35 (m, 2H);2.90-2.70 (m, 2H); 1.50-1.20 (m, 3H). Mass Spec detects 424 (M+H).

Example 334

Part A: Preparation of [(Methylthio)(3-acetylphenylamino)]methylenepropanedinitrile

[Bis(methylthio)methylene]propanedinitrile 3.00 g, 17.6 mmol, 1 eq.),and 3′ amino-acetophenone (2.38 g, 17.6 mmol, 1 eq.), were mixed andrefluxed under N₂ in ethanol for 16 hours. Solids precipitated whilecooling to 25° C. The solids were filtered. Obtained 1.86 g of tansolids.

M.P.=165.0-166.5° C. NMR (300 MHz, DMSO-d₆) δ 10.66 (m, 1H); 7.90-7.80(m, 2H); 7.60-7.50 (m, 2H); 2.60 (s, 3H); 2.54 (s, 3H).

Part B: Preparation of2-[(3-acetylanilino)({3-[4-(4-fluorobenzyl)-1-piperidinyl]propyl}amino)methylene]malononitrile

3-(4-(4-fluorophenylmethyl)piperidin-1-yl)propylamine, 49 mg, 0.194mmol, 1 eq.) and the product from Part A (50 mg, 0.194 mmol, 1 eq.) weremixed then stirred under N2 overnight. The reaction was stripped and theresidue purified over chloroform/methanol. Obtained 17 mg of a whiteamphorphous solid. NMR (300 MHz, CDCl₃) δ 7.82 (d, 1H, J=7 Hz); 7.73(s,1H); 7.51 (t, 1H, J=7 Hz); 7.34 (d, 1H, J=7Hz); 7.10-6.80 (m, 4H); 3.28(m, 2H); 2.62 (s, 3H); 2.64-2.40 (m,2H); 2.40-2.25 (m, 2H); 2.05-1.70(m, 2H); 1.70-1.35 (m, 3H); 1.20-0.80 (m, 2H). Mass Spec detects 460(M+H).

Example 335

Part A: Preparation ofN-[1-(methylthio)-2-nitroethenyl]-3-acetylbenzenamine

A neat mixture of 1,1-bismethylthio-2-nitroethylene (6.5 g, 38.5 mmol,10 eq) and 3-aminoacetophenone (0.5 g, 3.85 mmol, 1 eq) was meltedtogether and heated at 140° C. for four hours. The mixture was cooled toroom temperature, then subjected to flash chromatography, eluting with50% ethyl acetate/hexanes, to yield 0.63 g of a yellow powder asproduct. Yield=65%. NMR (300 MHz, CDCl₃) δ 11.82 (bs, 1H), 7.95-7.91 (m,2H), 7.59-7.48 (m, 2H), 6.73 (s, 1H), 2.65 (s, 3H), 2.41 (s, 3H).

Part B: Preparation of1-(3-{[(E)-1-({-[4-(4-fluorobenzyl)-1-piperidinyl]propyl}amino)-2-nitroethylenyl]amino}phenyl)ethanone

To a suspension of N-[1-(methylthio)-2-nitroethenyl]-3-acetylbenzenamine(0.30 g, 1.19 mmol, 1.00 eq) in 20 ml of methanol was added3-(4-fluorobenzyl)piperidin-1-yl)propylamine (0.31 g, 1.25 mmol, 1.05eq), and the mixture was stirred at room temperature. After three days,a colorless solution was observed. The solvent was removed in-vacuo, andthe residue was subjected to flash chromatography, eluting with 10%methanol/chloroform, to yield 0.38 g of an orange glass as product.Yield=70%.

NMR (300 MHz, CDCl₃) δ 10.51 (bs, 1H), 7.92 (d, 1H, j=8 Hz), 7.72 (bs,1H), 7.54 (dd, 1H, j=8 Hz, 8 Hz), 7.35 (bd, 1H), 6.90-6.88 (m, 5H), 6.17(s, 1H), 3.54 (bs, 2H), 2.92-2.84 (m, 2H), 2.63 (s, 3H), 2.51 (m, 2H),1.99-1.91 (m, 4H), 1.55-1.50 (m, 3H), 0.88-0.85 (m, 2H). MS (ESI)detects (M+H)⁺=455.

The following compounds can be prepared by procedures describedpreviously:

TABLE 3c

Mass Spec Core Z R3 M + 1 332 a N—CN 3-methoxyphenyl 424 333 a N—CN3-acetylphenyl 460 334 a C(CN)2 3-acetylphenyl 460 335 a CHNO23-acetylphenyl 455 336 b N—CN 3-acetylphenyl 436 337 b C(CN)23-acetylphenyl 460 338 b NCONH2 3-acetylphenyl 454 339 b CHNO23-acetylphenyl 455 340 b N—CN 3,5-diacetylphenyl 478 341 b NCONH23,5-diacetylphenyl 496 342 b NCO2CH3 3,5-diacetylphenyl 511 343 b C(CN)23,5-diacetylphenyl 344 b N—CN 3-(1-methyl-1H-tetrazol- 476 5-yl)phenyl345 b C(CN)2 3-(1-methyl-1H-tetrazol- 500 5-yl)phenyl 346 b NCONH23-(1-methyl-1H-tetrazol- 494 5-yl)phenyl 347 b N—CN 2,4-dimethoxy-phenyl454 348 b N—CN 5-acetyl-2-methoxy-phenyl 466 349 d N—CN3-(1-methyl-1H-tetrazol- 488 5-yl)phenyl 350 c N—CN phenyl 448 351 cN—CN 3-acetylphenyl 490 352 c N—CN 3-cyanophenyl 473 353 c N—CN2,4-dimethoxyphenyl 508 354 c N—CN 2,5-dimethoxyphenyl 508 355 c N—CN5-acetyl-2-methoxy-phenyl 520 356 c N—CN 2,4-dimethylphenyl 476 357 cN—CN 4-(1-methyl-1H-tetrazol- 530 5-yl)phenyl 358 c N—CN4-(1-propyl-1H-tetrazol- 558 5-yl)phenyl 359 c N—CN 5,6,7,8-tetrahydro-502 naphthy-2-yl-phenyl 360 c N—CN 4-(4-morpholinyl)-phenyl 533 361 CN—CN 2,5-dimethylphenyl 362 c N—CN 4-hydroxy-2-methylphenyl 363 c N—CN2-methylphenyl 364 c N—CN 2-phenylethyl 365 c N—CN 1-adamantyl 366 cN—CN 2-adamantyl 367 c C(CN)2 3-acetylphenyl 514 368 c C(CN)25-acetyl-2-methoxy-phenyl 544 369 c CHNO2 3-acetylphenyl 509 370 e CHNO23-acetylphenyl 560 371 e N—CN 3,5-diacetylphenyl 583 372 e N—CN3-acetylphenyl 541 373 e N—CN 4-(1-propyl-1H-tetrazol- 581 5-yl)phenyl

The following tables contain representative examples of the presentinvention, and may be prepared by procedures described above, or methodsfamiliar to one skilled in the art. Each entry in each table is intendedto be paired with each formulae at the start of the table. For example,Entry 1 in Table 4 is intended to be paired with each of formulae 1a-44.

TABLE 4*

Entry G R3 1 4-F—Ph Ph 2 4-F—Ph 3-CN—Ph 3 4-F—Ph 3-COCH3—Ph 4 4-F—Ph3-CO2Me—Ph 5 4-F—Ph 3-CO2Et—Ph 6 4-F—Ph 3-CO2H—Ph 7 4-F—Ph 3-CONH2—Ph 84-F—Ph 3-CONHMe—Ph 9 4-F—Ph 3-F—Ph 10 4-F—Ph 3-Cl—Ph 11 4-F—Ph 3-Br—Ph12 4-F—Ph 3-NO2—Ph 13 4-F—Ph 3-NH2—Ph 14 4-F—Ph 3-NHMe—Ph 15 4-F—Ph3-NMe2—Ph 16 4-F—Ph 3-NHCOCH3—Ph 17 4-F—Ph 3-SO2NH2—Ph 18 4-F—Ph3-SO2NHMe—Ph 19 4-F—Ph 3-CF3—Ph 20 4-F—Ph 3-OCH3—Ph 21 4-F—Ph 3-OPh—Ph22 4-F—Ph 3-OCF3—Ph 23 4-F—Ph 3-SCH3—Ph 24 4-F—Ph 3-SOCH3—Ph 25 4-F—Ph3-SO2CH3—Ph 26 4-F—Ph 3-OH—Ph 27 4-F—Ph 3-CH2OH—Ph 28 4-F—Ph3-CHOHCH3—Ph 29 4-F—Ph 3-COH(CH3)2—Ph 30 4-F—Ph 3-CHOHPh—Ph 31 4-F—Ph3-CH3—Ph 32 4-F—Ph 3-C2H5—Ph 33 4-F—Ph 3-iPr-Ph 34 4-F—Ph 3-tBu-Ph 354-F—Ph 3-Ph—Ph 36 4-F—Ph 3-CH2Ph—Ph 37 4-F—Ph 3-CH2CO2Me—Ph 38 4-F—Ph3-(1-piperidinyl)-Ph 39 4-F—Ph 3-(1-pyrrolidinyl)-Ph 40 4-F—Ph3-(2-imidazolyl)-Ph 41 4-F—Ph 3-(1-imidazolyl)-Ph 42 4-F—Ph3-(2-thiazolyl)-Ph 43 4-F—Ph 3-(3-pyrazolyl)-Ph 44 4-F—Ph3-(1-pyrazolyl)-Ph 45 4-F—Ph 3-(1-tetrazolyl)-Ph 46 4-F—Ph3-(5-tetrazolyl)-Ph 47 4-F—Ph 3-(2-pyridyl)-Ph 48 4-F—Ph3-(2-thienyl)-Ph 49 4-F—Ph 3-(2-furanyl)-Ph 50 4-F—Ph 4-CN—Ph 51 4-F—Ph4-COCH3—Ph 52 4-F—Ph 4-CO2Me—Ph 53 4-F—Ph 4-CO2Et—Ph 54 4-F—Ph 4-CO2H—Ph55 4-F—Ph 4-CONH2—Ph 56 4-F—Ph 4-CONHMe—Ph 57 4-F—Ph 4-CONHPh—Ph 584-F—Ph 4-NHCONH2—Ph 59 4-F—Ph 4-F—Ph 60 4-F—Ph 4-Cl—Ph 61 4-F—Ph 4-Br—Ph62 4-F—Ph 4-NO2—Ph 63 4-F—Ph 4-NH2—Ph 64 4-F—Ph 4-NHMe—Ph 65 4-F—Ph4-NMe2—Ph 66 4-F—Ph 4-NHCOCH3—Ph 67 4-F—Ph 4-SO2NH2—Ph 68 4-F—Ph4-SO2NHMe—Ph 69 4-F—Ph 4-CF3—Ph 70 4-F—Ph 4-OCH3—Ph 71 4-F—Ph 4-OPh—Ph72 4-F—Ph 4-OCF3—Ph 73 4-F—Ph 4-SCH3—Ph 74 4-F—Ph 4-SOCH3—Ph 75 4-F—Ph4-SO2CH3—Ph 76 4-F—Ph 4-OH—Ph 77 4-F—Ph 4-CH2OH—Ph 78 4-F—Ph4-CHOHCH3—Ph 79 4-F—Ph 4-COH(CH3)2—Ph 80 4-F—Ph 4-CH3—Ph 81 4-F—Ph4-C2H5—Ph 82 4-F—Ph 4-iPr-Ph 83 4-F—Ph 4-tBu-Ph 84 4-F—Ph 4-Ph—Ph 854-F—Ph 4-CH2Ph—Ph 86 4-F—Ph 4-CH2CO2Me—Ph 87 4-F—Ph 4-(1-piperidinyl)-Ph88 4-F—Ph 4-(1-pyrrolidinyl)-Ph 89 4-F—Ph 4-(2-imidazolyl)-Ph 90 4-F—Ph4-(1-imidazolyl)-Ph 91 4-F—Ph 4-(2-thiazolyl)-Ph 92 4-F—Ph4-(3-pyrazolyl)Ph 93 4-F—Ph 4-(1-pyrazolyl)-Ph 94 4-F—Ph4-(1-tetrazolyl)-Ph 95 4-F—Ph 4-(5-tetrazolyl)-Ph 96 4-F—Ph4-(2-pyridyl)-Ph 97 4-F—Ph 4-(2-thienyl)-Ph 98 4-F—Ph 4-(2-furanyl)-Ph99 4-F—Ph 2-CN—Ph 100 4-F—Ph 2-COCH3—Ph 101 4-F—Ph 2-CO2Me—Ph 102 4-F—Ph2-CO2Et—Ph 103 4-F—Ph 2-CO2H—Ph 104 4-F—Ph 2-CONH2—Ph 105 4-F—Ph2-CONHMe—Ph 106 4-F—Ph 2-F—Ph 107 4-F—Ph 2-Cl—Ph 108 4-F—Ph 2-Br—Ph 1094-F—Ph 2-NO2—Ph 110 4-F—Ph 2-NH2—Ph 111 4-F—Ph 2-NHMe—Ph 112 4-F—Ph2-NMe2—Ph 113 4-F—Ph 2-NHCOCH3—Ph 114 4-F—Ph 2-SO2NH2—Ph 115 4-F—Ph2-SO2NHMe—Ph 116 4-F—Ph 2-CF3—Ph 117 4-F—Ph 2-OCH3—Ph 118 4-F—Ph2-OPh—Ph 119 4-F—Ph 2-OCF3—Ph 120 4-F—Ph 2-SCH3—Ph 121 4-F—Ph 2-SOCH3—Ph122 4-F—Ph 2-SO2CH3—Ph 123 4-F—Ph 2-OH—Ph 124 4-F—Ph 2-CH2OH—Ph 1254-F—Ph 2-CHOHCH3—Ph 126 4-F—Ph 2-COH(CH3)2—Ph 127 4-F—Ph 2-CHOHPh—Ph 1284-F—Ph 2-CH3—Ph 129 4-F—Ph 2-C2H5—Ph 130 4-F—Ph 2-iPr-Ph 131 4-F—Ph2-tBu-Ph 132 4-F—Ph 2-Ph—Ph 133 4-F—Ph 2-CH2Ph—Ph 134 4-F—Ph2-CH2CO2Me—Ph 135 4-F—Ph 2-(1-piperidinyl)-Ph 136 4-F—Ph2-(1-pyrrolidinyl)-Ph 137 4-F—Ph 2-(2-imidazolyl)-Ph 138 4-F—Ph2-(1-imidazolyl)-Ph 139 4-F—Ph 2-(2-thiazolyl)-Ph 140 4-F—Ph2-(3-pyrazolyl)-Ph 141 4-F—Ph 2-(1-pyrazolyl)-Ph 142 4-F—Ph2-(1-tetrazolyl)-Ph 143 4-F—Ph 2-(5-tetrazolyl)-Ph 144 4-F—Ph2-(2-pyridyl)-Ph 145 4-F—Ph 2-(2-thienyl)-Ph 146 4-F—Ph 2-(2-furanyl)-Ph147 4-F—Ph 2,4-diF—Ph 148 4-F—Ph 2,5-diF—Ph 149 4-F—Ph 2,6-diF—Ph 1504-F—Ph 3,4-diF—Ph 151 4-F—Ph 3,5-diF—Ph 152 4-F—Ph 2,4-diCl—Ph 1534-F—Ph 2,5-diCl—Ph 154 4-F—Ph 2,6-diCl—Ph 155 4-F—Ph 3,4-diCl—Ph 1564-F—Ph 3,5-diCl—Ph 157 4-F—Ph 3,4-diCF3—Ph 158 4-F—Ph 3,5-diCF3—Ph 1594-F—Ph 5-Cl-2-MeO—Ph 160 4-F—Ph 5-Cl-2-Me—Ph 161 4-F—Ph 2-F-5-Me—Ph 1624-F—Ph 2-F-5-NO2—Ph 163 4-F—Ph 3,4-OCH2O—Ph 164 4-F—Ph 3,4-OCH2CH2O—Ph165 4-F—Ph 2-MeO-4-Me—Ph 166 4-F—Ph 2-MeO-5-Me—Ph 167 4-F—Ph 1-naphthyl168 4-F—Ph 2-naphthyl 169 4-F—Ph 2-thienyl 170 4-F—Ph 3-thienyl 1714-F—Ph 2-furanyl 172 4-F—Ph 3-furanyl 173 4-F—Ph 2-pyridyl 174 4-F—Ph3-pyridyl 175 4-F—Ph 4-pyridyl 176 4-F—Ph 2-indolyl 177 4-F—Ph 3-indolyl178 4-F—Ph 5-indolyl 179 4-F—Ph 6-indolyl 180 4-F—Ph 3-indazolyl 1814-F—Ph 5-indazolyl 182 4-F—Ph 6-indazolyl 183 4-F—Ph 2-imidazolyl 1844-F—Ph 3-pyrazolyl 185 4-F—Ph 2-thiazolyl 186 4-F—Ph 5-tetrazolyl 1874-F—Ph 2-benzimidazolyl 188 4-F—Ph 5-benzimidazolyl 189 4-F—Ph2-benzothiazolyl 190 4-F—Ph 5-benzothiazolyl 191 4-F—Ph 2-benzoxazolyl192 4-F—Ph 5-benzoxazolyl 193 4-F—Ph 1-adamantyl 194 4-F—Ph 2-adamantyl195 4-F—Ph t-Bu 196 2-F—Ph 3-CN—Ph 197 2-F—Ph 3-COCH3—Ph 198 2-F—Ph3-CO2Me—Ph 199 2-F—Ph 3-CO2Et—Ph 200 2-F—Ph 3-CO2H—Ph 201 2-F—Ph3-CONH2—Ph 202 2-F—Ph 3-F—Ph 203 2-F—Ph 3-Cl—Ph 204 2-F—Ph 3-NH2—Ph 2052-F—Ph 3-SO2NH2—Ph 206 2-F—Ph 3-CF3—Ph 207 2-F—Ph 3-OCH3—Ph 208 2-F—Ph3-OEt—Ph 209 2-F—Ph 3-OCF3—Ph 210 2-F—Ph 3-SO2CH3—Ph 211 2-F—Ph 3-OH—Ph212 2-F—Ph 3-CH3—Ph 213 2-F—Ph 3-C2H5—Ph 214 2-F—Ph 4-CN—Ph 215 2-F—Ph4-COCH3—Ph 216 2-F—Ph 4-CO2Me—Ph 217 2-F—Ph 4-CO2Et—Ph 218 2-F—Ph4-CO2H—Ph 219 2-F—Ph 4-CONH2—Ph 220 2-F—Ph 4-F—Ph 221 2-F—Ph 4-Cl—Ph 2222-F—Ph 4-NH2—Ph 223 2-F—Ph 4-SO2NH2—Ph 224 2-F—Ph 4-CF3—Ph 225 2-F—Ph4-OCH3—Ph 226 2-F—Ph 4-OEt—Ph 227 2-F—Ph 4-OCF3—Ph 228 2-F—Ph4-SO2CH3—Ph 229 2-F—Ph 4-OH—Ph 230 2-F—Ph 4-CH3—Ph 231 2-F—Ph 4-C2H5—Ph232 2-F—Ph 2,4-diF—Ph 233 2-F—Ph 2, 5-diF—Ph 234 2-F—Ph 3,4-diF—Ph 2352-F—Ph 3,5-diF—Ph 236 2-F—Ph 2,4-diCl—Ph 237 2-F—Ph 2,5-diCl—Ph 2382-F—Ph 3,4-diCl—Ph 239 2-F—Ph 3,5-diCl—Ph 240 2-F—Ph 3,4-OCH2O—Ph 2412-F—Ph 3,4-OCH2CH2O—Ph 242 2-F—Ph 2-thienyl 243 2-F—Ph 2-furanyl 2442-F—Ph 2-pyridyl 245 2-F—Ph 4-pyridyl 246 2-F—Ph 2-imidazolyl 247 2-F—Ph3-pyrazolyl 248 2-F—Ph 2-thiazolyl 249 2-F—Ph 5-tetrazolyl 250 2-F—Ph1-adamantyl 251 2,4-diF—Ph 3-CN—Ph 252 2,4-diF—Ph 3-COCH3—Ph 2532,4-diF—Ph 3-CO2Me—Ph 254 2,4-diF—Ph 3-CO2Et—Ph 255 2,4-diF—Ph 3-CO2H—Ph256 2,4-diF—Ph 3-CONH2—Ph 257 2,4-diF—Ph 3-F—Ph 258 2,4-diF—Ph 3-Cl—Ph259 2,4-diF—Ph 3-NH2—Ph 260 2,4-diF—Ph 3-SO2NH2—Ph 261 2,4-diF—Ph3-CF3—Ph 262 2,4-diF—Ph 3-OCH3—Ph 263 2,4-diF—Ph 3-OEt—Ph 264 2,4-diF—Ph3-OCF3—Ph 265 2,4-diF—Ph 3-SO2CH3—Ph 266 2,4-diF—Ph 3-OH—Ph 2672,4-diF—Ph 3-CH3—Ph 268 2,4-diF—Ph 3-C2H5—Ph 269 2,4-diF—Ph 4-CN—Ph 2702,4-diF—Ph 4-COCH3—Ph 271 2,4-diF—Ph 4-CO2Me—Ph 272 2,4-diF—Ph4-CO2Et—Ph 273 2,4-diF—Ph 4-CO2H—Ph 274 2,4-diF—Ph 4-CONH2—Ph 2752,4-diF—Ph 4-F—Ph 276 2,4-diF—Ph 4-Cl—Ph 277 2,4-diF—Ph 4-NH2—Ph 2782,4-diF—Ph 4-SO2NH2—Ph 279 2,4-diF—Ph 4-CF3—Ph 280 2,4-diF—Ph 4-OCH3—Ph281 2,4-diF—Ph 4-OEt—Ph 282 2,4-diF—Ph 4-OCF3—Ph 283 2,4-diF—Ph4-SO2CH3—Ph 284 2,4-diF—Ph 4-OH—Ph 285 2,4-diF—Ph 4-CH3—Ph 2862,4-diF—Ph 4-C2H5—Ph 287 2,4-diF—Ph 2,4-diF—Ph 288 2,4-diF—Ph 2,5-diF—Ph289 2,4-diF—Ph 3,4-diF—Ph 290 2,4-diF—Ph 3,5-diF—Ph 291 2,4-diF—Ph2,4-diCl—Ph 292 2,4-diF—Ph 2,5-diCl—Ph 293 2,4-diF—Ph 3,4-diCl—Ph 2942,4-diF—Ph 3,5-diCl—Ph 295 2,4-diF—Ph 3,4-OCH2O—Ph 296 2,4-diF—Ph3,4-OCH2CH2O—Ph 297 2,4-diF—Ph 2-thienyl 298 2,4-diF—Ph 2-furanyl 2992,4-diF—Ph 2-pyridyl 300 2,4-diF—Ph 4-pyridyl 301 2,4-diF—Ph2-imidazolyl 302 2,4-diF—Ph 3-pyrazolyl 303 2,4-diF—Ph 2-thiazolyl 3042,4-diF—Ph 5-tetrazolyl 305 2,4-diF—Ph 1-adamantyl 306 4-Cl—Ph Ph 3074-Cl—Ph 3-CN—Ph 308 4-Cl—Ph 3-COCH3—Ph 309 4-Cl—Ph 3-CO2Me—Ph 3104-Cl—Ph 3-CO2Et—Ph 311 4-Cl—Ph 3-CO2H—Ph 312 4-Cl—Ph 3-CONH2—Ph 3134-Cl—Ph 3-CONHMe—Ph 314 4-Cl—Ph 3-F—Ph 315 4-Cl—Ph 3-Cl—Ph 316 4-Cl—Ph3-Br—Ph 317 4-Cl—Ph 3-NO2—Ph 318 4-Cl—Ph 3-NH2—Ph 319 4-Cl—Ph 3-NHMe—Ph320 4-Cl—Ph 3-NMe2—Ph 321 4-Cl—Ph 3-NHCOCH3—Ph 322 4-Cl—Ph 3-SO2NH2—Ph323 4-Cl—Ph 3-SO2NHMe—Ph 324 4-Cl—Ph 3-CF3—Ph 325 4-Cl—Ph 3-OCH3—Ph 3264-Cl—Ph 3-OPh—Ph 327 4-Cl—Ph 3-OCF3—Ph 328 4-Cl—Ph 3-SCH3—Ph 329 4-Cl—Ph3-SOCH3—Ph 330 4-Cl—Ph 3-SO2CH3—Ph 331 4-Cl—Ph 3-OH—Ph 332 4-Cl—Ph3-CH2OH—Ph 333 4-Cl—Ph 3-CHOHCH3—Ph 334 4-Cl—Ph 3-COH(CH3)2—Ph 3354-Cl—Ph 3-CHOHPh—Ph 336 4-Cl—Ph 3-CH3—Ph 337 4-Cl—Ph 3-C2H5—Ph 3384-Cl—Ph 3-iPr-Ph 339 4-Cl—Ph 3-tBu-Ph 340 4-Cl—Ph 3-Ph—Ph 341 4-Cl—Ph3-CH2Ph—Ph 342 4-Cl—Ph 3-CH2CO2Me—Ph 343 4-Cl—Ph 3-(1-piperidinyl)-Ph344 4-Cl—Ph 3-(1-pyrrolidinyl)-Ph 345 4-Cl—Ph 3-(2-imidazolyl)-Ph 3464-Cl—Ph 3-(1-imidazolyl)-Ph 347 4-Cl—Ph 3-(2-thiazolyl)-Ph 348 4-Cl—Ph3-(3-pyrazolyl)-Ph 349 4-Cl—Ph 3-(1-pyrazolyl)-Ph 350 4-Cl—Ph3-(1-tetrazolyl)-Ph 351 4-Cl—Ph 3-(5-tetrazolyl)-Ph 352 4-Cl—Ph3-(2-pyridyl)-Ph 353 4-Cl—Ph 3-(2-thienyl)-Ph 354 4-Cl—Ph3-(2-furanyl)-Ph 355 4-Cl—Ph 4-CN—Ph 356 4-Cl—Ph 4-COCH3—Ph 357 4-Cl—Ph4-CO2Me—Ph 358 4-Cl—Ph 4-CO2Et—Ph 359 4-Cl—Ph 4-CO2H—Ph 360 4-Cl—Ph4-CONH2—Ph 361 4-Cl—Ph 4-CONHMe—Ph 362 4-Cl—Ph 4-CONHPh—Ph 363 4-Cl—Ph4-NHCONH2—Ph 364 4-Cl—Ph 4-F—Ph 365 4-Cl—Ph 4-Cl—Ph 366 4-Cl—Ph 4-Br—Ph367 4-Cl—Ph 4-NO2—Ph 368 4-Cl—Ph 4-NH2—Ph 369 4-Cl—Ph 4-NHMe—Ph 3704-Cl—Ph 4-NMe2—Ph 371 4-Cl—Ph 4-NHCOCH3—Ph 372 4-Cl—Ph 4-SO2NH2—Ph 3734-Cl—Ph 4-SO2NHMe—Ph 374 4-Cl—Ph 4-CF3—Ph 375 4-Cl—Ph 4-OCH3—Ph 3764-Cl—Ph 4-OPh—Ph 377 4-Cl—Ph 4-OCF3—Ph 378 4-Cl—Ph 4-SCH3—Ph 379 4-Cl—Ph4-SOCH3—Ph 380 4-Cl—Ph 4-SO2CH3—Ph 381 4-Cl—Ph 4-OH—Ph 382 4-Cl—Ph4-CH2OH—Ph 383 4-Cl—Ph 4-CHOHCH3—Ph 384 4-Cl—Ph 4-COH(CH3)2—Ph 3854-Cl—Ph 4-CH3—Ph 386 4-Cl—Ph 4-C2H5—Ph 387 4-Cl—Ph 4-iPr-Ph 388 4-Cl—Ph4-tBu-Ph 389 4-Cl—Ph 4-Ph—Ph 390 4-Cl—Ph 4-CH2Ph—Ph 391 4-Cl—Ph4-CH2CO2Me—Ph 392 4-Cl—Ph 4-(1-piperidinyl)-Ph 393 4-Cl—Ph4-(1-pyrrolidinyl)-Ph 394 4-Cl—Ph 4-(2-imidazolyl)-Ph 395 4-Cl—Ph4-(1-imidazolyl)-Ph 396 4-Cl—Ph 4-(2-thiazolyl)-Ph 397 4-Cl—Ph4-(3-pyrazolyl)-Ph 398 4-Cl—Ph 4-(1-pyrazolyl)-Ph 399 4-Cl—Ph4-(1-tetrazolyl)-Ph 400 4-Cl—Ph 4-(5-tetrazolyl)-Ph 401 4-Cl—Ph4-(2-pyridyl)-Ph 402 4-Cl—Ph 4-(2-thienyl)-Ph 403 4-Cl—Ph4-(2-furanyl)-Ph 404 4-Cl—Ph 2-CN—Ph 405 4-Cl—Ph 2-COCH3—Ph 406 4-Cl—Ph2-CO2Me—Ph 407 4-Cl—Ph 2-CO2Et—Ph 408 4-Cl—Ph 2-CO2H—Ph 409 4-Cl—Ph2-CONH2—Ph 410 4-Cl—Ph 2-CONHMe—Ph 411 4-Cl—Ph 2-F—Ph 412 4-Cl—Ph2-Cl—Ph 413 4-Cl—Ph 2-Br—Ph 414 4-Cl—Ph 2-NO2—Ph 415 4-Cl—Ph 2-NH2—Ph416 4-Cl—Ph 2-NHMe—Ph 417 4-Cl—Ph 2-NMe2—Ph 418 4-Cl—Ph 2-NHCOCH3—Ph 4194-Cl—Ph 2-SO2NH2—Ph 420 4-Cl—Ph 2-SO2NHMe—Ph 421 4-Cl—Ph 2-CF3—Ph 4224-Cl—Ph 2-OCH3—Ph 423 4-Cl—Ph 2-OPh—Ph 424 4-Cl—Ph 2-OCF3—Ph 425 4-Cl—Ph2-SCH3—Ph 426 4-Cl—Ph 2-SOCH3—Ph 427 4-Cl—Ph 2-SO2CH3—Ph 428 4-Cl—Ph2-OH—Ph 429 4-Cl—Ph 2-CH2OH—Ph 430 4-Cl—Ph 2-CHOHCH3—Ph 431 4-Cl—Ph2-COH(CH3)2—Ph 432 4-Cl—Ph 2-CHOHPh—Ph 433 4-Cl—Ph 2-CH3—Ph 434 4-Cl—Ph2-C2H5—Ph 435 4-Cl—Ph 2-iPr-Ph 436 4-Cl—Ph 2-tBu-Ph 437 4-Cl—Ph 2-Ph—Ph438 4-Cl—Ph 2-CH2Ph—Ph 439 4-Cl—Ph 2-CH2CO2Me—Ph 440 4-Cl—Ph2-(1-piperidinyl)-Ph 441 4-Cl—Ph 2-(1-pyrrolidinyl)-Ph 442 4-Cl—Ph2-(2-imidazolyl)-Ph 443 4-Cl—Ph 2-(1-imidazolyl)-Ph 444 4-Cl—Ph2-(2-thiazolyl)-Ph 445 4-Cl—Ph 2-(3-pyrazolyl)-Ph 446 4-Cl—Ph2-(1-pyrazolyl)-Ph 447 4-Cl—Ph 2-(1-tetrazolyl)-Ph 448 4-Cl—Ph2-(5-tetrazolyl)-Ph 449 4-Cl—Ph 2-(2-pyridyl)-Ph 450 4-Cl—Ph2-(2-thienyl)-Ph 451 4-Cl—Ph 2-(2-furanyl)-Ph 452 4-Cl—Ph 2,4-diF—Ph 4534-Cl—Ph 2,5-diF—Ph 454 4-Cl—Ph 2,6-diF—Ph 455 4-Cl—Ph 3,4-diF—Ph 4564-Cl—Ph 3,5-diF—Ph 457 4-Cl—Ph 2,4-diCl—Ph 458 4-Cl—Ph 2,5-diCl—Ph 4594-Cl—Ph 2,6-diCl—Ph 460 4-Cl—Ph 3,4-diCl—Ph 461 4-Cl—Ph 3,5-diCl—Ph 4624-Cl—Ph 3,4-diCF3—Ph 463 4-Cl—Ph 3,5-diCF3—Ph 464 4-Cl—Ph 5-Cl-2-MeO—Ph465 4-Cl—Ph 5-Cl-2-Me—Ph 466 4-Cl—Ph 2-F-5-Me—Ph 467 4-Cl—Ph2-F-5-NO2—Ph 468 4-Cl—Ph 3,4-OCH2O—Ph 469 4-Cl—Ph 3,4-OCH2CH2O—Ph 4704-Cl—Ph 2-MeO-4-Me—Ph 471 4-Cl—Ph 2-MeO-5-Me—Ph 472 4-Cl—Ph 1-naphthyl473 4-Cl—Ph 2-naphthyl 474 4-Cl—Ph 2-thienyl 475 4-Cl—Ph 3-thienyl 4764-Cl—Ph 2-furanyl 477 4-Cl—Ph 3-furanyl 478 4-Cl—Ph 2-pyridyl 4794-Cl—Ph 3-pyridyl 480 4-Cl—Ph 4-pyridyl 481 4-Cl—Ph 2-indolyl 4824-Cl—Ph 3-indolyl 483 4-Cl—Ph 5-indolyl 484 4-Cl—Ph 6-indolyl 4854-Cl—Ph 3-indazolyl 486 4-Cl—Ph 5-indazolyl 487 4-Cl—Ph 6-indazolyl 4884-Cl—Ph 2-imidazolyl 489 4-Cl—Ph 3-pyrazolyl 490 4-Cl—Ph 2-thiazolyl 4914-Cl—Ph 5-tetrazolyl 492 4-Cl—Ph 2-benzimidazolyl 493 4-Cl—Ph5-benzimidazolyl 494 4-Cl—Ph 2-benzothiazolyl 495 4-Cl—Ph5-benzothiazolyl 496 4-Cl—Ph 2-benzoxazolyl 497 4-Cl—Ph 5-benzoxazolyl498 4-Cl—Ph 1-adamantyl 499 4-Cl—Ph 2-adamantyl 500 4-Cl—Ph t-Bu 5012-Cl—Ph 3-CN—Ph 502 2-Cl—Ph 3-COCH3—Ph 503 2-Cl—Ph 3-CO2Me—Ph 5042-Cl—Ph 3-CO2Et—Ph 505 2-Cl—Ph 3-CO2H—Ph 506 2-Cl—Ph 3-CONH2—Ph 5072-Cl—Ph 3-F—Ph 508 2-Cl—Ph 3-Cl—Ph 509 2-Cl—Ph 3-NH2—Ph 510 2-Cl—Ph3-SO2NH2—Ph 511 2-Cl—Ph 3-CF3—Ph 512 2-Cl—Ph 3-OCH3—Ph 513 2-Cl—Ph3-OEt—Ph 514 2-Cl—Ph 3-OCF3—Ph 515 2-Cl—Ph 3-SO2CH3—Ph 516 2-Cl—Ph3-OH—Ph 517 2-Cl—Ph 3-CH3—Ph 518 2-Cl—Ph 3-C2H5—Ph 519 2-Cl—Ph 4-CN—Ph520 2-Cl—Ph 4-COCH3—Ph 521 2-Cl—Ph 4-CO2Me—Ph 522 2-Cl—Ph 4-CO2Et—Ph 5232-Cl—Ph 4-CO2H—Ph 524 2-Cl—Ph 4-CONH2—Ph 525 2-Cl—Ph 4-F—Ph 526 2-Cl—Ph4-Cl—Ph 527 2-Cl—Ph 4-NH2—Ph 528 2-Cl—Ph 4-SO2NH2—Ph 529 2-Cl—Ph4-CF3—Ph 530 2-Cl—Ph 4-OCH3—Ph 531 2-Cl—Ph 4-OEt—Ph 532 2-Cl—Ph4-OCF3—Ph 533 2-Cl—Ph 4-SO2CH3—Ph 534 2-Cl—Ph 4-OH—Ph 535 2-Cl—Ph4-CH3—Ph 536 2-Cl—Ph 4-C2H5—Ph 537 2-Cl—Ph 2,4-diF—Ph 538 2-Cl—Ph2,5-diF—Ph 539 2-Cl—Ph 3,4-diF—Ph 540 2-Cl—Ph 3,5-diF—Ph 541 2-Cl—Ph2,4-diCl—Ph 542 2-Cl—Ph 2,5-diCl—Ph 543 2-Cl—Ph 3,4-diCl—Ph 544 2-Cl—Ph3,5-diCl—Ph 545 2-Cl—Ph 3,4-OCH2O—Ph 546 2-Cl—Ph 3,4-OCH2CH2O—Ph 5472-Cl—Ph 2-thienyl 548 2-Cl—Ph 2-furanyl 549 2-Cl—Ph 2-pyridyl 5502-Cl—Ph 4-pyridyl 551 2-Cl—Ph 2-imidazolyl 552 2-Cl—Ph 3-pyrazolyl 5532-Cl—Ph 2-thiazolyl 554 2-Cl—Ph 5-tetrazolyl 555 2-Cl—Ph 1-adamantyl 5562,4-diCl—Ph 3-CN—Ph 557 2,4-diCl—Ph 3-COCH3—Ph 558 2,4-diCl—Ph3-CO2Me—Ph 559 2,4-diCl—Ph 3-CO2Et—Ph 560 2,4-diCl—Ph 3-CO2H—Ph 5612,4-diCl—Ph 3-CONH2—Ph 562 2,4-diCl—Ph 3-F—Ph 563 2,4-diCl—Ph 3-Cl—Ph564 2,4-diCl—Ph 3-NH2—Ph 565 2,4-diCl—Ph 3-SO2NH2—Ph 566 2,4-diCl—Ph3-CF3—Ph 567 2,4-diCl—Ph 3-OCH3—Ph 568 2,4-diCl—Ph 3-OEt—Ph 5692,4-diCl—Ph 3-OCF3—Ph 570 2,4-diCl—Ph 3-SO2CH3—Ph 571 2,4-diCl—Ph3-OH—Ph 572 2,4-diCl—Ph 3-CH3—Ph 573 2,4-diCl—Ph 3-C2H5—Ph 5742,4-diCl—Ph 4-CN—Ph 575 2,4-diCl—Ph 4-COCH3—Ph 576 2,4-diCl—Ph4-CO2Me—Ph 577 2,4-diCl—Ph 4-CO2Et—Ph 578 2,4-diCl—Ph 4-CO2H—Ph 5792,4-diCl—Ph 4-CONH2—Ph 580 2,4-diCl—Ph 4-F—Ph 581 2,4-diCl—Ph 4-Cl—Ph582 2,4-diCl—Ph 4-NH2—Ph 583 2,4-diCl—Ph 4-SO2NH2—Ph 584 2,4-diCl—Ph4-CF3—Ph 585 2,4-diCl—Ph 4-OCH3—Ph 586 2,4-diCl—Ph 4-OEt—Ph 5872,4-diCl—Ph 4-OCF3—Ph 588 2,4-diCl—Ph 4-SO2CH3—Ph 589 2,4-diCl—Ph4-OH—Ph 590 2,4-diCl—Ph 4-CH3—Ph 591 2,4-diCl—Ph 4-C2H5—Ph 5922,4-diCl—Ph 2,4-diF—Ph 593 2,4-diCl—Ph 2,5-diF—Ph 594 2,4-diCl—Ph3,4-diF—Ph 595 2,4-diCl—Ph 3,5-diF—Ph 596 2,4-diCl—Ph 2,4-diCl—Ph 5972,4-diCl—Ph 2,5-diCl—Ph 598 2,4-diCl—Ph 3,4-diCl—Ph 599 2,4-diCl—Ph3,5-diCl—Ph 600 2,4-diCl—Ph 3,4-OCH2O—Ph 601 2,4-diCl—Ph 3,4-OCH2CH2O—Ph602 2,4-diCl—Ph 2-thienyl 603 2,4-diCl—Ph 2-furanyl 604 2,4-diCl—Ph2-pyridyl 605 2,4-diCl—Ph 4-pyridyl 606 2,4-diCl—Ph 2-imidazolyl 6072,4-diCl—Ph 3-pyrazolyl 608 2,4-diCl—Ph 2-thiazolyl 609 2,4-diCl—Ph5-tetrazolyl 610 2,4-diCl—Ph 1-adamantyl 611 3-OCH3—Ph 3-CN—Ph 6123-OCH3—Ph 3-COCH3—Ph 613 3-OCH3—Ph 3 -CO2Me—Ph 614 3-OCH3—Ph 3-CO2Et—Ph615 3-OCH3—Ph 3-CO2H—Ph 616 3-OCH3—Ph 3-CONH2—Ph 617 3-OCH3—Ph 3-F—Ph618 3-OCH3—Ph 3-Cl—Ph 619 3-OCH3—Ph 3-NH2—Ph 620 3-OCH3—Ph 3-SO2NH2—Ph621 3-OCH3—Ph 3-CF3—Ph 622 3-OCH3—Ph 3-OCH3—Ph 623 3-OCH3—Ph 3-OEt—Ph624 3-OCH3—Ph 3-OCF3—Ph 625 3-OCH3—Ph 3-SO2CH3—Ph 626 3-OCH3—Ph 3-OH—Ph627 3-OCH3—Ph 3-CH3—Ph 628 3-OCH3—Ph 3-C2H5—Ph 629 3-OCH3—Ph 4-CN—Ph 6303-OCH3—Ph 4-COCH3—Ph 631 3-OCH3—Ph 4-CO2Me—Ph 632 3-OCH3—Ph 4-CO2Et—Ph633 3-OCH3—Ph 4-CO2H—Ph 634 3-OCH3—Ph 4-CONH2—Ph 635 3-OCH3—Ph 4-F—Ph636 3-OCH3—Ph 4-Cl—Ph 637 3-OCH3—Ph 4-NH2—Ph 638 3-OCH3—Ph 4-SO2NH2—Ph639 3-OCH3—Ph 4-CF3—Ph 640 3-OCH3—Ph 4-OCH3—Ph 641 3-OCH3—Ph 4-OEt—Ph642 3-OCH3—Ph 4-OCF3—Ph 643 3-OCH3—Ph 4-SO2CH3—Ph 644 3-OCH3—Ph 4-OH—Ph645 3-OCH3—Ph 4-CH3—Ph 646 3-OCH3—Ph 4-C2H5—Ph 647 3-OCH3—Ph 2,4-diF—Ph648 3-OCH3—Ph 2,5-diF—Ph 649 3-OCH3—Ph 3,4-diF—Ph 650 3-OCH3—Ph3,5-diF—Ph 651 3-OCH3—Ph 2,4-diCl—Ph 652 3-OCH3—Ph 2,5-diCl—Ph 6533-OCH3—Ph 3,4-diCl—Ph 654 3-OCH3—Ph 3,5-diCl—Ph 655 3-OCH3—Ph3,4-OCH2O—Ph 656 3-OCH3—Ph 3,4-OCH2CH2O—Ph 657 3-OCH3—Ph 2-thienyl 6583-OCH3—Ph 2-furanyl 659 3-OCH3—Ph 2-pyridyl 660 3-OCH3—Ph 4-pyridyl 6613-OCH3—Ph 2-imidazolyl 662 3-OCH3—Ph 3-pyrazolyl 663 3-OCH3—Ph2-thiazolyl 664 3-OCH3—Ph 5-tetrazolyl 665 3-OCH3—Ph 1-adamantyl 6662-thienyl 3-CN—Ph 667 2-thienyl 3-COCH3—Ph 668 2-thienyl 3-F—Ph 6692-thienyl 3-Cl—Ph 670 2-thienyl 3-NH2—Ph 671 2-thienyl 3-OCH3—Ph 6722-thienyl 3-OH—Ph 673 2-thienyl 4-CN—Ph 674 2-thienyl 4-COCH3—Ph 6752-thienyl 4-F—Ph 676 2-thienyl 4-Cl—Ph 677 2-thienyl 4-NH2—Ph 6782-thienyl 4-OCH3—Ph 679 2-thienyl 4-OH—Ph 680 2-thienyl 3,4-diF—Ph 6812-thienyl 3,5-diF—Ph 682 2-thienyl 3,4-diCl—Ph 683 2-thienyl 3,5-diCl—Ph684 2-thienyl 3,4-OCH2O—Ph 685 2-thienyl 3,4-OCH2CH2O—Ph 686 3-thienyl3-CN—Ph 687 3-thienyl 3-COCH3—Ph 688 3-thienyl 3-F—Ph 689 3-thienyl3-Cl—Ph 690 3-thienyl 3-NH2—Ph 691 3-thienyl 3-OCH3—Ph 692 3-thienyl3-OH—Ph 693 3-thienyl 4-CN—Ph 694 3-thienyl 4-COCH3—Ph 695 3-thienyl4-F—Ph 696 3-thienyl 4-Cl—Ph 697 3-thienyl 4-NH2—Ph 698 3-thienyl4-OCH3—Ph 699 3-thienyl 4-OH—Ph 700 3-thienyl 3,4-diF—Ph 701 3-thienyl3,5-diF—Ph 702 3-thienyl 3,4-diCl—Ph 703 3-thienyl 3,5-diCl—Ph 7043-thienyl 3,4-OCH2O—Ph 705 3-thienyl 3,4-OCH2CH2O—Ph 706 2-furanyl3-CN—Ph 707 2-furanyl 3-COCH3—Ph 708 2-furanyl 3-F—Ph 709 2-furanyl3-Cl—Ph 710 2-furanyl 3-NH2—Ph 711 2-furanyl 3-OCH3—Ph 712 2-furanyl3-OH—Ph 713 2-furanyl 4-CN—Ph 714 2-furanyl 4-COCH3—Ph 715 2-furanyl4-F—Ph 716 2-furanyl 4-Cl—Ph 717 2-furanyl 4-NH2—Ph 718 2-furanyl4-OCH3—Ph 719 2-furanyl 4-OH—Ph 720 2-furanyl 3,4-diF—Ph 721 2-furanyl3,5-diF—Ph 722 2-furanyl 3,4-diCl—Ph 723 2-furanyl 3,5-diCl—Ph 7242-furanyl 3,4-OCH2O—Ph 725 2-furanyl 3,4-OCH2CH2O—Ph 726 3-furanyl3-CN—Ph 727 3-furanyl 3-COCH3—Ph 728 3-furanyl 3-F—Ph 729 3-furanyl3-Cl—Ph 730 3-furanyl 3-NH2—Ph 731 3-furanyl 3-OCH3—Ph 732 3-furanyl3-OH—Ph 733 3-furanyl 4-CN—Ph 734 3-furanyl 4-COCH3—Ph 735 3-furanyl4-F—Ph 736 3-furanyl 4-Cl—Ph 737 3-furanyl 4-NH2—Ph 738 3-furanyl4-OCH3—Ph 739 3-furanyl 4-OH—Ph 740 3-furanyl 3,4-diF—Ph 741 3-furanyl3,5-diF—Ph 742 3-furanyl 3, 4-diCl—Ph 743 3-furanyl 3,5-diCl—Ph 7443-furanyl 3,4-OCH2O—Ph 745 3-furanyl 3,4-OCH2CH2O—Ph 746 2-pyridyl3-CN—Ph 747 2-pyridyl 3-COCH3—Ph 748 2-pyridyl 3-F—Ph 749 2-pyridyl3-Cl—Ph 750 2-pyridyl 3-NH2—Ph 751 2-pyridyl 3-OCH3—Ph 752 2-pyridyl3-OH—Ph 753 2-pyridyl 4-CN—Ph 754 2-pyridyl 4-COCH3—Ph 755 2-pyridyl4-F—Ph 756 2-pyridyl 4-Cl—Ph 757 2-pyridyl 4-NH2—Ph 758 2-pyridyl4-OCH3—Ph 759 2-pyridyl 4-OH—Ph 760 2-pyridyl 3,4-diF—Ph 761 2-pyridyl3,5-diF—Ph 762 2-pyridyl 3,4-diCl—Ph 763 2-pyridyl 3,5-diCl—Ph 7642-pyridyl 3,4-OCH2O—Ph 765 2-pyridyl 3,4-OCH2CH2O—Ph 766 3-pyridyl3CN—Ph 767 3-pyridyl 3-COCH3—Ph 768 3-pyridyl 3-F—Ph 769 3-pyridyl3-Cl—Ph 770 3-pyridyl 3-NH2—Ph 771 3-pyridyl 3-OCH3—Ph 772 3-pyridyl3-OH—Ph 773 3-pyridyl 4-CN—Ph 774 3-pyridyl 4-COCH3—Ph 775 3-pyridyl4-F—Ph 776 3-pyridyl 4-Cl—Ph 777 3-pyridyl 4-NH2—Ph 778 3-pyridyl4-OCH3—Ph 779 3-pyridyl 4-OH—Ph 780 3-pyridyl 3,4-diF—Ph 781 3-pyridyl3,5-diF—Ph 782 3-pyridyl 3,4-diCl—Ph 783 3-pyridyl 3,5-diCl—Ph 7843-pyridyl 3,4-OCH2O—Ph 785 3-pyridyl 3,4-OCH2CH2O—Ph 786 4-pyridyl3-CN—Ph 787 4-pyridyl 3-COCH3—Ph 788 4-pyridyl 3-F—Ph 789 4-pyridyl3-Cl—Ph 790 4-pyridyl 3-NH2—Ph 791 4-pyridyl 3-OCH3—Ph 792 4-pyridyl3-OH—Ph 793 4-pyridyl 4-CN—Ph 794 4-pyridyl 4-COCH3—Ph 795 4-pyridyl4-F—Ph 796 4-pyridyl 4-Cl—Ph 797 4-pyridyl 4-NH2—Ph 798 4-pyridyl4-OCH3—Ph 799 4-pyridyl 4-OH—Ph 800 4-pyridyl 3,4-diF—Ph 801 4-pyridyl3, 5-diF—Ph 802 4-pyridyl 3,4-diCl—Ph 803 4-pyridyl 3,5-diCl—Ph 8044-pyridyl 3,4-OCH2O—Ph 805 4-pyridyl 3,4-OCH2CH2O—Ph 806 3-indolyl3-CN—Ph 807 3-indolyl 3-COCH3—Ph 808 3-indolyl 3-F—Ph 809 3-indolyl3-Cl—Ph 810 3-indolyl 3-NH2—Ph 811 3-indolyl 3-OCH3—Ph 812 3-indolyl3-OH—Ph 813 3-indolyl 4-CN—Ph 814 3-indolyl 4-COCH3—Ph 815 3-indolyl4-F—Ph 816 3-indolyl 4-Cl—Ph 817 3-indolyl 4-NH2—Ph 818 3-indolyl4-OCH3—Ph 819 3-indolyl 4-OH—Ph 820 3-indolyl 3,4-diF—Ph 821 3-indolyl3,5-diF—Ph 822 3-indolyl 3,4-diCl—Ph 823 3-indolyl 3,5-diCl—Ph 8243-indolyl 3,4-OCH2O—Ph 825 3-indolyl 3,4-OCH2CH2O—Ph 826 5-indolyl3-CN—Ph 827 5-indolyl 3-COCH3—Ph 828 5-indolyl 3-F—Ph 829 5-indolyl3-Cl—Ph 830 5-indolyl 3-NH2—Ph 831 5-indolyl 3-OCH3—Ph 832 5-indolyl3-OH—Ph 833 5-indolyl 4-CN—Ph 834 5-indolyl 4-COCH3—Ph 835 5-indolyl4-F—Ph 836 5-indolyl 4-Cl—Ph 837 5-indolyl 4-NH2—Ph 838 5-indolyl4-OCH3—Ph 839 5-indolyl 4-OH—Ph 840 5-indolyl 3,4-diF—Ph 841 5-indolyl3,5-diF—Ph 842 5-indolyl 3,4-diCl—Ph 843 5-indolyl 3,5-diCl—Ph 8445-indolyl 3,4-OCH2O—Ph 845 5-indolyl 3,4-OCH2CH2O—Ph 846 5-indazolyl3-CN—Ph 847 5-indazolyl 3-COCH3—Ph 848 5-indazolyl 3-F—Ph 8495-indazolyl 3-Cl—Ph 850 5-indazolyl 3-NH2—Ph 851 5-indazolyl 3-OCH3—Ph852 5-indazolyl 3-OH—Ph 853 5-indazolyl 4-CN—Ph 854 5-indazolyl4-COCH3—Ph 855 5-indazolyl 4-F—Ph 856 5-indazolyl 4-Cl—Ph 8575-indazolyl 4-NH2—Ph 858 5-indazolyl 4-OCH3—Ph 859 5-indazolyl 4-OH—Ph860 5-indazolyl 3,4-diF—Ph 861 5-indazolyl 3,5-diF—Ph 862 5-indazolyl3,4-diCl—Ph 863 5-indazolyl 3,5-diCl—Ph 864 5-indazolyl 3,4-OCH2O—Ph 8655-indazolyl 3,4-OCH2CH2O—Ph 866 5-benzimidazolyl 3-CN—Ph 8675-benzimidazolyl 3-COCH3—Ph 868 5-benzimidazolyl 3-F—Ph 8695-benzimidazolyl 3-Cl—Ph 870 5-benzimidazolyl 3-NH2—Ph 8715-benzimidazolyl 3-OCH3—Ph 872 5-benzimidazolyl 3-OH—Ph 8735-benzimidazolyl 4-CN—Ph 874 5-benzimidazolyl 4-COCH3—Ph 8755-benzimidazolyl 4-F—Ph 876 5-benzimidazolyl 4-Cl—Ph 8775-benzimidazolyl 4-NH2—Ph 878 5-benzimidazolyl 4-OCH3—Ph 8795-benzimidazolyl 4-OH—Ph 880 5-benzimidazolyl 3,4-diF—Ph 8815-benzimidazolyl 3,5-diF—Ph 882 5-benzimidazolyl 3,4-diCl—Ph 8835-benzimidazolyl 3,5-diCl—Ph 884 5-benzimidazolyl 3,4-OCH2O—Ph 8855-benzimidazolyl 3,4-OCH2CH2O—Ph 886 5-benzothiazolyl 3-CN—Ph 8875-benzothiazolyl 3-COCH3—Ph 888 5-benzothiazolyl 3-F—Ph 8895-benzothiazolyl 3-Cl—Ph 890 5-benzothiazolyl 3-NH2—Ph 8915-benzothiazolyl 3-OCH3—Ph 892 5-benzothiazolyl 3-OH—Ph 8935-benzothiazolyl 4-CN—Ph 894 5-benzothiazolyl 4-COCH3—Ph 8955-benzothiazolyl 4-F—Ph 896 5-benzothiazolyl 4-Cl—Ph 8975-benzothiazolyl 4-NH2—Ph 898 5-benzothiazolyl 4-OCH3—Ph 8995-benzothiazolyl 4-OH—Ph 900 5-benzothiazolyl 3,4-diF—Ph 9015-benzothiazolyl 3,5-diF—Ph 902 5-benzothiazolyl 3,4-diCl—Ph 9035-benzothiazolyl 3,5-diCl—Ph 904 5-benzothiazolyl 3,4-OCH2O—Ph 9055-benzothiazolyl 3,4-OCH2CH2O—Ph 906 5-benzoxazolyl 3-CN—Ph 9075-benzoxazolyl 3-COCH3—Ph 908 5-benzoxazolyl 3-F—Ph 909 5-benzoxazolyl3-Cl—Ph 910 5-benzoxazolyl 3-NH2—Ph 911 5-benzoxazolyl 3-OCH3—Ph 9125-benzoxazolyl 3-OH—Ph 913 5-benzoxazolyl 4-CN—Ph 914 5-benzoxazolyl4-COCH3—Ph 915 5-benzoxazolyl 4-F—Ph 916 5-benzoxazolyl 4-Cl—Ph 9175-benzoxazolyl 4-NH2—Ph 918 5-benzoxazolyl 4-OCH3—Ph 919 5-benzoxazolyl4-OH—Ph 920 5-benzoxazolyl 3,4-diF—Ph 921 5-benzoxazolyl 3,5-diF—Ph 9225-benzoxazolyl 3,4-diCl—Ph 923 5-benzoxazolyl 3,5-diCl—Ph 9245-benzoxazolyl 3,4-OCH2O—Ph 925 5-benzoxazolyl 3,4-OCH2CH2O—Ph

TABLE 6*

Entry R³ R¹⁴ 1 Ph CN 2 Ph F 3 Ph Cl 4 Ph CH2OH 5 Ph OH 6 Ph NH2 7 PhCO2Me 8 Ph CO2Et 9 Ph CONH2 10 Ph NHPh 11 Ph NHMe 12 Ph OMe 13 PhC(O)(2-imidazolyl) 14 Ph C(O)(4-imidazolyl) 15 Ph C(O)(2-thiazolyl) 16Ph C(O)(4-thiazolyl) 17 Ph C(O)(2-oxazolyl) 18 Ph C(O)(4-oxazolyl) 19 PhC(O)(3-pyrazolyl) 20 Ph C(O)(4-pyrazolyl) 21 Ph C(O)(5-tetrazolyl) 22 PhC(O)(2-pyridyl) 23 Ph C(O)(3-pyridyl) 24 Ph C(O)(4-pyridyl) 25 PhC(O)(2-thienyl) 26 Ph C(O)(3-thienyl) 27 Ph C(O)(2-furanyl) 28 PhC(O)(3-furanyl) 29 Ph 2-thienyl 30 Ph 3-thienyl 31 Ph 2-furanyl 32 Ph3-furanyl 33 Ph 2-pyridyl 34 Ph 3-pyridyl 35 Ph 4-pyridyl 36 Ph1-imidazolyl 37 Ph 2-imidazolyl 38 Ph 4-imidazolyl 39 Ph 1-pyrazolyl 40Ph 3-pyrazolyl 41 Ph 4-pyrazolyl 42 Ph 2-thiazolyl 43 Ph 4-thiazolyl 44Ph 5-tetrazolyl 45 Ph 2-oxazolyl 46 Ph 4-oxazolyl 47 PhC(O)N(2-imidazolyl) 48 Ph C(O)N(4-imidazolyl) 49 Ph C(O)N(2-thiazolyl)50 Ph C(O)14(4-thiazolyl) 51 Ph C(O)N(2-oxazolyl) 52 PhC(O)N(4-oxazolyl) 53 Ph C(O)N(3-pyrazolyl) 54 Ph C(O)N(4-pyrazolyl) 55Ph C(O)N(2-pyridyl) 56 Ph C(O)N(3-pyridyl) 57 Ph C(O)N(4-pyridyl) 58 PhC(O)N(2-thienyl) 59 Ph C(O)N(3-thienyl) 60 Ph C(O)N(2-furanyl) 61 PhC(O)N(3-furanyl) 62 Ph C(O)N(2-pyrrolyl) 63 Ph C(O)N(3-pyrrolyl) 64 PhCH2(1-imidazolyl) 65 Ph CH2(1-(1,2,3-triazolyl)) 66 PhCH2(2-(1,2,3-triazolyl)) 67 Ph CH2(1-(1,2,4-triazolyl)) 68 PhCH2(1-pyrazolyl) 69 3-CN—Ph CN 70 3-CN—Ph F 71 3-CN—Ph Cl 72 3-CN—PhCH2OH 73 3-CN—Ph OH 74 3-CN—Ph NH2 75 3-CN—Ph CO2Me 76 3-CN—Ph CO2Et 773-CN—Ph CONH2 78 3-CN—Ph NHPh 79 3-CN—Ph NHMe 80 3-CN—Ph OMe 81 3-CN—PhC(O)(2-imidazolyl) 82 3-CN—Ph C(O)(4-imidazolyl) 83 3-CN—PhC(O)(2-thiazolyl) 84 3-CN—Ph C(O)(4-thiazolyl) 85 3-CN—PhC(O)(2-oxazolyl) 86 3-CN—Ph C(O)(4-oxazolyl) 87 3-CN—PhC(O)(3-pyrazolyl) 88 3-CN—Ph C(O)(4-pyrazolyl) 89 3-CN—PhC(O)(5-tetrazolyl) 90 3-CN—Ph C(O)(2-pyridyl) 91 3-CN—Ph C(O)(3-pyridyl)92 3-CN—Ph C(O)(4-pyridyl) 93 3-CN—Ph C(O)(2-thienyl) 94 3-CN—PhC(O)(3-thienyl) 95 3-CN—Ph C(O)(2-furanyl) 96 3-CN—Ph C(O)(3-furanyl) 973-CN—Ph 2-thienyl 98 3-CN—Ph 3-thienyl 99 3-CN—Ph 2-furanyl 100 3-CN—Ph3-furanyl 101 3-CN—Ph 2-pyridyl 102 3-CN—Ph 3-pyridyl 103 3-CN—Ph4-pyridyl 104 3-CN—Ph 1-imidazolyl 105 3-CN—Ph 2-imidazolyl 106 3-CN—Ph4-imidazolyl 107 3-CN—Ph 1-pyrazolyl 108 3-CN—Ph 3-pyrazolyl 109 3-CN—Ph4-pyrazolyl 110 3-CN—Ph 2-thiazolyl 111 3-CN—Ph 4-thiazolyl 112 3-CN—Ph5-tetrazolyl 113 3-CN—Ph 2-oxazolyl 114 3-CN—Ph 4-oxazolyl 115 3-CN—PhC(O)N(2-imidazolyl) 116 3-CN—Ph C(O)N(4-imidazolyl) 117 3-CN—PhC(O)N(2-thiazolyl) 118 3-CN—Ph C(O)N(4-thiazolyl) 119 3-CN—PhC(O)N(2-oxazolyl) 120 3-CN—Ph C(O)N(4-oxazolyl) 121 3-CN—PhC(O)N(3-pyrazolyl) 122 3-CN—Ph C(O)N(4-pyrazolyl) 123 3-CN—PhC(O)N(2-pyridyl) 124 3-CN—Ph C(O)N(3-pyridyl) 125 3-CN—PhC(O)N(4-pyridyl) 126 3-CN—Ph C(O)N(2-thienyl) 127 3-CN—PhC(O)N(3-thienyl) 128 3-CN—Ph C(O)N(2-furanyl) 129 3-CN—PhC(O)N(3-furanyl) 130 3-CN—Ph C(O)N(2-pyrrolyl) 131 3-CN—PhC(O)N(3-pyrrolyl) 132 3-CN—Ph CH2(1-imidazolyl) 133 3-CN—PhCH2(1-(1,2,3-triazolyl)) 134 3-CN—Ph CH2(2-(1,2,3-triazolyl)) 1353-CN—Ph CH2(1-(1,2,4-triazolyl)) 136 3-CN—Ph CH2(1-pyrazolyl) 1373-OMe—Ph CN 138 3-OMe—Ph F 139 3-OMe—Ph Cl 140 3-OMe—Ph CH2OH 1413-OMe—Ph OH 142 3-OMe—Ph NH2 143 3-OMe—Ph CO2Me 144 3-OMe—Ph CO2Et 1453-OMe—Ph CONH2 146 3-OMe—Ph NHPh 147 3-OMe—Ph NHMe 148 3-OMe—Ph OMe 1493-OMe—Ph C(O)(2-imidazolyl) 150 3-OMe—Ph C(O)(4-imidazolyl) 151 3-OMe—PhC(O)(2-thiazolyl) 152 3-OMe—Ph C(O)(4-thiazolyl) 153 3-OMe—PhC(O)(2-oxazolyl) 154 3-OMe—Ph C(O)(4-oxazolyl) 155 3-OMe—PhC(O)(3-pyrazolyl) 156 3-OMe—Ph C(O)(4-pyrazolyl) 157 3-OMe—PhC(O)(5-tetrazolyl) 158 3-OMe—Ph C(O)(2-pyridyl) 159 3-OMe—PhC(O)(3-pyridyl) 160 3-OMe—Ph C(O)(4-pyridyl) 161 3-OMe—PhC(O)(2-thienyl) 162 3-OMe—Ph C(O)(3-thienyl) 163 3-OMe—PhC(O)(2-furanyl) 164 3-OMe—Ph C(O)(3-furanyl) 165 3-OMe—Ph 2-thienyl 1663-OMe—Ph 3-thienyl 167 3-OMe—Ph 2-furanyl 168 3-OMe—Ph 3-furanyl 1693-OMe—Ph 2-pyridyl 170 3-OMe—Ph 3-pyridyl 171 3-OMe—Ph 4-pyridyl 1723-OMe—Ph 1-imidazolyl 173 3-OMe—Ph 2-imidazolyl 174 3-OMe—Ph4-imidazolyl 175 3-OMe—Ph 1-pyrazolyl 176 3-OMe—Ph 3-pyrazolyl 1773-OMe—Ph 4-pyrazolyl 178 3-OMe—Ph 2-thiazolyl 179 3-OMe—Ph 4-thiazolyl180 3-OMe—Ph 5-tetrazolyl 181 3-OMe—Ph 2-oxazolyl 182 3-OMe—Ph4-oxazolyl 183 3-OMe—Ph C(O)N(2-imidazolyl) 184 3-OMe—PhC(O)N(4-imidazolyl) 185 3-OMe—Ph C(O)N(2-thiazolyl) 186 3-OMe—PhC(O)N(4-thiazolyl) 187 3-OMe—Ph C(O)N(2-oxazolyl) 188 3-OMe—PhC(O)N(4-oxazolyl) 189 3-OMe—Ph C(O)N(3-pyrazolyl) 190 3-OMe—PhC(O)N(4-pyrazolyl) 191 3-OMe—Ph C(O)N(2-pyridyl) 192 3-OMe—PhC(O)N(3-pyridyl) 193 3-OMe—Ph C(O)N(4-pyridyl) 194 3-OMe—PhC(O)N(2-thienyl) 195 3-OMe—Ph C(O)N(3-thienyl) 196 3-OMe—PhC(O)N(2-furanyl) 197 3-OMe—Ph C(O)N(3-furanyl) 198 3-OMe—PhC(O)N(2-pyrrolyl) 199 3-OMe—Ph C(O)N(3-pyrrolyl) 200 3-OMe—PhCH2(1-imidazolyl) 201 3-OMe—Ph CH2(1-(1,2,3-triazolyl)) 202 3-OMe—PhCH2(2-(1,2,3-triazolyl)) 203 3-OMe—Ph CH2(1-(1,2,4-triazolyl)) 2043-OMe—Ph CH2(1-pyrazolyl) 205 3-C(O)Me—Ph CN 206 3-C(O)Me—Ph F 2073-C(O)Me—Ph Cl 208 3-C(O)Me—Ph CH2OH 209 3-C(O)Me—Ph OH 210 3-C(O)Me—PhNH2 211 3-C(O)Me—Ph CO2Me 212 3-C(O)Me—Ph CO2Et 213 3-C(O)Me—Ph CONH2214 3-C(O)Me—Ph NHPh 215 3-C(O)Me—Ph NHMe 216 3-C(O)Me—Ph OMe 2173-C(O)Me—Ph C(O)(2-imidazolyl) 218 3-C(O)Me—Ph C(O)(4-imidazolyl) 2193-C(O)Me—Ph C(O)(2-thiazolyl) 220 3-C(O)Me—Ph C(O)(4-thiazolyl) 2213-C(O)Me—Ph C(O)(2-oxazolyl) 222 3-C(O)Me—Ph C(O)(4-oxazolyl) 2233-C(O)Me—Ph C(O)(3-pyrazolyl) 224 3-C(O)Me—Ph C(O)(4-pyrazolyl) 2253-C(O)Me—Ph C(O)(5-tetrazolyl) 226 3-C(O)Me—Ph C(O)(2-pyridyl) 2273-C(O)Me—Ph C(O)(3-pyridyl) 228 3-C(O)Me—Ph C(O)(4-pyridyl) 2293-C(O)Me—Ph C(O)(2-thienyl) 230 3-C(O)Me—Ph C(O)(3-thienyl) 2313-C(O)Me—Ph C(O)(2-furanyl) 232 3-C(O)Me—Ph C(O)(3-furanyl) 2333-C(O)Me—Ph 2-thienyl 234 3-C(O)Me—Ph 3-thienyl 235 3-C(O)Me—Ph2-furanyl 236 3-C(O)Me—Ph 3-furanyl 237 3-C(O)Me—Ph 2-pyridyl 2383-C(O)Me—Ph 3-pyridyl 239 3-C(O)Me—Ph 4-pyridyl 240 3-C(O)Me—Ph1-imidazolyl 241 3-C(O)Me—Ph 2-imidazolyl 242 3-C(O)Me—Ph 4-imidazolyl243 3-C(O)Me—Ph 1-pyrazolyl 244 3-C(O)Me—Ph 3-pyrazolyl 245 3-C(O)Me—Ph4-pyrazolyl 246 3-C(O)Me—Ph 2-thiazolyl 247 3-C(O)Me—Ph 4-thiazolyl 2483-C(O)Me—Ph 5-tetrazolyl 249 3-C(O)Me—Ph 2-oxazolyl 250 3-C(O)Me—Ph4-oxazolyl 251 3-C(O)He—Ph C(O)N(2-imidazolyl) 252 3-C(O)Me—PhC(O)N(4-imidazolyl) 253 3-C(O)Me—Ph C(O)N(2-thiazolyl) 254 3-C(O)Me—PhC(O)N(4-thiazolyl) 255 3-C(O)Me—Ph C(O)N(2-oxazolyl) 256 3-C(O)Me—PhC(O)N(4-oxazolyl) 257 3-C(O)Me—Ph C(O)N(3-pyrazolyl) 258 3-C(O)Me—PhC(O)N(4-pyrazolyl) 259 3-C(O)Me—Ph C(O)N(2-pyridyl) 260 3-C(O)Me—PhC(O)N(3-pyridyl) 261 3-C(O)Me—Ph C(O)N(4-pyridyl) 262 3-C(O)Me—PhC(O)N(2-thienyl) 263 3-C(O)Me—Ph C(O)N(3-thienyl) 264 3-C(O)Me—PhC(O)N(2-furanyl) 265 3-C(O)Me—Ph C(O)N(3-furanyl) 266 3-C(O)Me—PhC(O)N(2-pyrrolyl) 267 3-C(O)Me—Ph C(O)N(3-pyrrolyl) 268 3-C(O)Me—PhCH2(1-imidazolyl) 269 3-C(O)Me—Ph CH2(1-(1,2,3-triazolyl)) 2703-C(O)Me—Ph CH2(2-(1,2,3-triazolyl)) 271 3-C(O)Me—PhCH2(1-(1,2,4-triazolyl)) 272 3-C(O)Me—Ph CH2(1-pyrazolyl) 273 4-F—Ph CN274 4-F—Ph F 275 4-F—Ph Cl 276 4-F—Ph CH2OH 277 4-F—Ph OH 278 4-F—Ph NH2279 4-F—Ph CO2Me 280 4-F—Ph CO2Et 281 4-F—Ph CONH2 282 4-F—Ph NHPh 2834-F—Ph NHMe 284 4-F—Ph OMe 285 4-F—Ph C(O)(2-imidazolyl) 286 4-F—PhC(O)(4-imidazolyl) 287 4-F—Ph C(O)(2-thiazolyl) 288 4-F—PhC(O)(4-thiazolyl) 289 4-F—Ph C(O)(2-oxazolyl) 290 4-F—PhC(O)(4-oxazolyl) 291 4-F—Ph C(O)(3-pyrazolyl) 292 4-F—PhC(O)(4-pyrazolyl) 293 4-F—Ph C(O)(5-tetrazolyl) 294 4-F—PhC(O)(2-pyridyl) 295 4-F—Ph C(O)(3-pyridyl) 296 4-F—Ph C(O)(4-pyridyl)297 4-F—Ph C(O)(2-thienyl) 298 4-F—Ph C(O)(3-thienyl) 299 4-F—PhC(O)(2-furanyl) 300 4-F—Ph C(O)(3-furanyl) 301 4-F—Ph 2-thienyl 3024-F—Ph 3-thienyl 303 4-F—Ph 2-furanyl 304 4-F—Ph 3-furanyl 305 4-F—Ph2-pyridyl 306 4-F—Ph 3-pyridyl 307 4-F—Ph 4-pyridyl 308 4-F—Ph1-imidazolyl 309 4-F—Ph 2-imidazolyl 310 4-F—Ph 4-imidazolyl 311 4-F—Ph1-pyrazolyl 312 4-F—Ph 3-pyrazolyl 313 4-F—Ph 4-pyrazolyl 314 4-F—Ph2-thiazolyl 315 4-F—Ph 4-thiazolyl 316 4-F—Ph 5-tetrazolyl 317 4-F—Ph2-oxazolyl 318 4-F—Ph 4-oxazolyl 319 4-F—Ph C(O)N(2-imidazolyl) 3204-F—Ph C(O)N(4-imidazolyl) 321 4-F—Ph C(O)N(2-thiazolyl) 322 4-F—PhC(O)N(4-thiazolyl) 323 4-F—Ph C(O)N(2-oxazolyl) 324 4-F—PhC(O)N(4-oxazolyl) 325 4-F—Ph C(O)N(3-pyrazolyl) 326 4-F—PhC(O)N(4-pyrazolyl) 327 4-F—Ph C(O)N(2-pyridyl) 328 4-F—PhC(O)N(3-pyridyl) 329 4-F—Ph C(O)N(4-pyridyl) 330 4-F—Ph C(O)N(2-thienyl)331 4-F—Ph C(O)N(3-thienyl) 332 4-F—Ph C(O)N(2-furanyl) 333 4-F—PhC(O)N(3-furanyl) 334 4-F—Ph C(O)N(2-pyrrolyl) 335 4-F—PhC(O)N(3-pyrrolyl) 336 4-F—Ph CH2(1-imidazolyl) 337 4-F—PhCH2(1-(1,2,3-triazolyl)) 338 4-F—Ph CH2(2-(1,2,3-triazolyl)) 339 4-F—PhCH2(1-(1,2,4-triazolyl)) 340 4-F—Ph CH2(1-pyrazolyl)

TABLE 7

R1 = a) H, b) methyl, c) ethyl, d) n-propyl, e) allyl, f) n-butyl, g)n-pentyl, and h) n-hexyl. Entry G R3 1 4-F—Ph Ph 2 4-F—Ph 3-CN—Ph 34-F—Ph 3-COCH3—Ph 4 4-F—Ph 3-CO2Me—Ph 5 4-F—Ph 3-CO2Et—Ph 6 4-F—Ph3-CO2H—Ph 7 4-F—Ph 3-CONH2—Ph 8 4-F—Ph 3-CONHMe—Ph 9 4-F—Ph 3-F—Ph 104-F—Ph 3-Cl—Ph 11 4-F—Ph 3-Br—Ph 12 4-F—Ph 3-NO2—Ph 13 4-F—Ph 3-NH2—Ph14 4-F—Ph 3-NHMe—Ph 15 4-F—Ph 3-NMe2—Ph 16 4-F—Ph 3-NHCOCH3—Ph 17 4-F—Ph3-SO2NH2—Ph 18 4-F—Ph 3-SO2NHMe—Ph 19 4-F—Ph 3-CF3—Ph 20 4-F—Ph3-OCH3—Ph 21 4-F—Ph 3-OPh—Ph 22 4-F—Ph 3-OCF3—Ph 23 4-F—Ph 3-SCH3—Ph 244-F—Ph 3-SOCH3—Ph 25 4-F—Ph 3-SO2CH3—Ph 26 4-F—Ph 3-OH—Ph 27 4-F—Ph3-CH2OH—Ph 28 4-F—Ph 3-CHOHCH3—Ph 29 4-F—Ph 3-COH(CH3)2—Ph 30 4-F—Ph3-CHOHPh—Ph 31 4-F—Ph 3-CH3—Ph 32 4-F—Ph 3-C2H5—Ph 33 4-F—Ph 3-iPr-Ph 344-F—Ph 3-tBu-Ph 35 4-F—Ph 3-Ph—Ph 36 4-F—Ph 3-CH2Ph—Ph 37 4-F—Ph3-CH2CO2Me—Ph 38 4-F—Ph 3-(1-piperidinyl)-Ph 39 4-F—Ph3-(1-pyrrolidinyl)-Ph 40 4-F—Ph 3-(2-imidazolyl)-Ph 41 4-F—Ph3-(1-imidazolyl)-Ph 42 4-F—Ph 3-(2-thiazolyl)-Ph 43 4-F—Ph3-(3-pyrazolyl)-Ph 44 4-F—Ph 3-(1-pyrazolyl)-Ph 45 4-F—Ph3-(1-tetrazol)-Ph 46 4-F—Ph 3-(5-tetrazolyl)-Ph 47 4-F—Ph3-(2-pyridyl)-Ph 48 4-F—Ph 3-(2-thienyl)-Ph 49 4-F—Ph 3-(2-furanyl)-Ph50 4-F—Ph 4-CN—Ph 51 4-F—Ph 4-COCH3—Ph 52 4-F—Ph 4-CO2Me—Ph 53 4-F—Ph4-CO2Et—Ph 54 4-F—Ph 4-CO2H—Ph 55 4-F—Ph 4-CONH2—Ph 56 4-F—Ph4-CONHMe—Ph 57 4-F—Ph 4-CONHPh—Ph 58 4-F—Ph 4-NHCONH2—Ph 59 4-F—Ph4-F—Ph 60 4-F—Ph 4-Cl—Ph 61 4-F—Ph 4-Br—Ph 62 4-F—Ph 4-NO2—Ph 63 4-F—Ph4-NH2—Ph 64 4-F—Ph 4-NHMe—Ph 65 4-F—Ph 4-NMe2—Ph 66 4-F—Ph 4-NHCOCH3—Ph67 4-F—Ph 4-SO2NH2—Ph 68 4-F—Ph 4-SO2NHMe—Ph 69 4-F—Ph 4-CF3—Ph 704-F—Ph 4-OCH3—Ph 71 4-F—Ph 4-OPh—Ph 72 4-F—Ph 4-OCF3—Ph 73 4-F—Ph4-SCH3—Ph 74 4-F—Ph 4-SOCH3—Ph 75 4-F—Ph 4-SO2CH3—Ph 76 4-F—Ph 4-OH—Ph77 4-F—Ph 4-CH2OH—Ph 78 4-F—Ph 4-CHOHCH3—Ph 79 4-F—Ph 4-COH(CH3)2—Ph 804-F—Ph 4-CH3—Ph 81 4-F—Ph 4-C2H5—Ph 82 4-F—Ph 4-iPr-Ph 83 4-F—Ph4-tBu-Ph 84 4-F—Ph 4-Ph—Ph 85 4-F—Ph 4-CH2Ph—Ph 86 4-F—Ph 4-CH2CO2Me—Ph87 4-F—Ph 4-(1-piperidinyl)-Ph 88 4-F—Ph 4-(1-pyrrolidinyl)-Ph 89 4-F—Ph4-(2-imidazolyl)-Ph 90 4-F—Ph 4-(1-imidazolyl)-Ph 91 4-F—Ph4-(2-thiazolyl)-Ph 92 4-F—Ph 4-(3-pyrazolyl)-Ph 93 4-F—Ph4-(1-pyrazolyl)-Ph 94 4-F—Ph 4-(1-tetrazolyl)-Ph 95 4-F—Ph4-(5-tetrazolyl)-Ph 96 4-F—Ph 4-(2-pyridyl)-Ph 97 4-F—Ph4-(2-thienyl)-Ph 98 4-F—Ph 4-(2-furanyl)-Ph 99 4-F—Ph 2-CN—Ph 100 4-F—Ph2-COCH3—Ph 101 4-F—Ph 2-CO2Me—Ph 102 4-F—Ph 2-CO2Et—Ph 103 4-F—Ph2-CO2H—Ph 104 4-F—Ph 2-CONH2—Ph 105 4-F—Ph 2-CONHMe—Ph 106 4-F—Ph 2-F—Ph107 4-F—Ph 2-Cl—Ph 108 4-F—Ph 2-Br—Ph 109 4-F—Ph 2-NO2—Ph 110 4-F—Ph2-NH2—Ph 111 4-F—Ph 2-NHMe—Ph 112 4-F—Ph 2-NMe2—Ph 113 4-F—Ph2-NHCOCH3—Ph 114 4-F—Ph 2-SO2NH2—Ph 115 4-F—Ph 2-SO2NHMe—Ph 116 4-F—Ph2-CF3—Ph 117 4-F—Ph 2-OCH3—Ph 118 4-F—Ph 2-OPh—Ph 119 4-F—Ph 2-OCF3—Ph120 4-F—Ph 2-SCH3—Ph 121 4-F—Ph 2-SOCH3—Ph 122 4-F—Ph 2-SO2CH3—Ph 1234-F—Ph 2-OH—Ph 124 4-F—Ph 2-CH2OH—Ph 125 4-F—Ph 2-CHOHCH3—Ph 126 4-F—Ph2-COH(CH3)2—Ph 127 4-F—Ph 2-CHOHPh—Ph 128 4-F—Ph 2-CH3—Ph 129 4-F—Ph2-C2H5—Ph 130 4-F—Ph 2-iPr-Ph 131 4-F—Ph 2-tBu-Ph 132 4-F—Ph 2-Ph—Ph 1334-F—Ph 2-CH2Ph—Ph 134 4-F—Ph 2-CH2CO2Me—Ph 135 4-F—Ph2-(1-piperidinyl)-Ph 136 4-F—Ph 2-(1-pyrrolidinyl)-Ph 137 4-F—Ph2-(2-imidazolyl)-Ph 138 4-F—Ph 2-(1-imidazolyl)-Ph 139 4-F—Ph2-(2-thiazolyl)-Ph 140 4-F—Ph 2-(3-pyrazolyl)-Ph 141 4-F—Ph2-(1-pyrazolyl)-Ph 142 4-F—Ph 2-(1-tetrazolyl)-Ph 143 4-F—Ph2-(5-tetrazolyl)-Ph 144 4-F—Ph 2-(2-pyridyl)-Ph 145 4-F—Ph2-(2-thienyl)-Ph 146 4-F—Ph 2-(2-furanyl)-Ph 147 4-F—Ph 2,4-diF—Ph 1484-F—Ph 2,5-diF—Ph 149 4-F—Ph 2,6-diF—Ph 150 4-F—Ph 3,4-diF—Ph 151 4-F—Ph3,5-diF—Ph 152 4-F—Ph 2,4-diCl—Ph 153 4-F—Ph 2,5-diCl—Ph 154 4-F—Ph2,6-diCl—Ph 155 4-F—Ph 3,4-diCl—Ph 156 4-F—Ph 3,5-diCl—Ph 157 4-F—Ph3,4-diCF3—Ph 158 4-F—Ph 3,5-diCF3—Ph 159 4-F—Ph 5-Cl-2-MeO—Ph 160 4-F—Ph5-Cl-2-Me—Ph 161 4-F—Ph 2-F-5-Me—Ph 162 4-F—Ph 2-F-5-NO2—Ph 163 4-F—Ph3,4-OCH2O—Ph 164 4-F—Ph 3,4-OCH2CH2O—Ph 165 4-F—Ph 2-MeO-4-Me—Ph 1664-F—Ph 2-MeO-5-Me—Ph 167 4-F—Ph 1-naphthyl 168 4-F—Ph 2-naphthyl 1694-F—Ph 2-thienyl 170 4-F—Ph 3-thienyl 171 4-F—Ph 2-furanyl 172 4-F—Ph3-furanyl 173 4-F—Ph 2-pyridyl 174 4-F—Ph 3-pyridyl 175 4-F—Ph 4-pyridyl176 4-F—Ph 2-indolyl 177 4-F—Ph 3-indolyl 178 4-F—Ph 5-indolyl 1794-F—Ph 6-indolyl 180 4-F—Ph 3-indazolyl 181 4-F—Ph 5-indazolyl 1824-F—Ph 6-indazolyl 183 4-F—Ph 2-imidazolyl 184 4-F—Ph 3-pyrazolyl 1854-F—Ph 2-thiazolyl 186 4-F—Ph 5-tetrazolyl 187 4-F—Ph 2-benzimidazolyl188 4-F—Ph 5-benzimidazolyl 189 4-F—Ph 2-benzothiazolyl 190 4-F—Ph5-benzothiazolyl 191 4-F—Ph 2-benzoxazolyl 192 4-F—Ph 5-benzoxazolyl 1934-F—Ph 1-adamantyl 194 4-F—Ph 2-adamantyl 195 4-F—Ph t-Bu 196 2-F—Ph3-CN—Ph 197 2-F—Ph 3-COCH3—Ph 198 2-F—Ph 3-CO2Me—Ph 199 2-F—Ph3-CO2Et—Ph 200 2-F—Ph 3-CO2H—Ph 201 2-F—Ph 3-CONH2—Ph 202 2-F—Ph 3-F—Ph203 2-F—Ph 3-Cl—Ph 204 2-F—Ph 3-NH2—Ph 205 2-F—Ph 3-SO2NH2—Ph 206 2-F—Ph3-CF3—Ph 207 2-F—Ph 3-OCH3—Ph 208 2-F—Ph 3-OEt—Ph 209 2-F—Ph 3-OCF3—Ph210 2-F—Ph 3-SO2CH3—Ph 211 2-F—Ph 3-OH—Ph 212 2-F—Ph 3-CH3—Ph 213 2-F—Ph3-C2H5—Ph 214 2-F—Ph 4-CN—Ph 215 2-F—Ph 4-COCH3—Ph 216 2-F—Ph 4-CO2Me—Ph217 2-F—Ph 4-CO2Et—Ph 218 2-F—Ph 4-CO2H—Ph 219 2-F—Ph 4-CONH2—Ph 2202-F—Ph 4-F—Ph 221 2-F—Ph 4-Cl—Ph 222 2-F—Ph 4-NH2—Ph 223 2-F—Ph4-SO2NH2—Ph 224 2-F—Ph 4-CF3—Ph 225 2-F—Ph 4-OCH3—Ph 226 2-F—Ph 4-OEt—Ph227 2-F—Ph 4-OCF3—Ph 228 2-F—Ph 4-SO2CH3—Ph 229 2-F—Ph 4-OH—Ph 2302-F—Ph 4-CH3—Ph 231 2-F—Ph 4-C2H5—Ph 232 2-F—Ph 2,4-diF—Ph 233 2-F—Ph2,5-diF—Ph 234 2-F—Ph 3,4-diF—Ph 235 2-F—Ph 3,5-diF—Ph 236 2-F—Ph2,4-diCl—Ph 237 2-F—Ph 2,5-diCl—Ph 238 2-F—Ph 3,4-diCl—Ph 239 2-F—Ph3,5-diCl—Ph 240 2-F—Ph 3,4-OCH2O—Ph 241 2-F—Ph 3,4-OCH2CH2O—Ph 2422-F—Ph 2-thienyl 243 2-F—Ph 2-furanyl 244 2-F—Ph 2-pyridyl 245 2-F—Ph4-pyridyl 246 2-F—Ph 2-imidazolyl 247 2-F—Ph 3-pyrazolyl 248 2-F—Ph2-thiazolyl 249 2-F—Ph 5-tetrazolyl 250 2-F—Ph 1-adamantyl 2512,4-diF—Ph 3-CN—Ph 252 2,4-diF—Ph 3-COCH3—Ph 253 2,4-diF—Ph 3-CO2Me—Ph254 2,4-diF—Ph 3-CO2Et—Ph 255 2,4-diF—Ph 3-CO2H—Ph 256 2,4-diF—Ph3-CONH2—Ph 257 2,4-diF—Ph 3-F—Ph 258 2,4-diF—Ph 3-Cl—Ph 259 2,4-diF—Ph3-NH2—Ph 260 2,4-diF—Ph 3-SO2NH2—Ph 261 2,4-diF—Ph 3-CF3—Ph 2622,4-diF—Ph 3-OCH3—Ph 263 2,4-diF—Ph 3-OEt—Ph 264 2,4-diF—Ph 3-OCF3—Ph265 2,4-diF—Ph 3-SO2CH3—Ph 266 2,4-diF—Ph 3-OH—Ph 267 2,4-diF—Ph3-CH3—Ph 268 2,4-diF—Ph 3-C2H5—Ph 269 2,4-diF—Ph 4-CN—Ph 270 2,4-diF—Ph4-COCH3—Ph 271 2,4-diF—Ph 4-CO2Me—Ph 272 2,4-diF—Ph 4-CO2Et—Ph 2732,4-diF—Ph 4-CO2H—Ph 274 2,4-diF—Ph 4-CONH2—Ph 275 2,4-diF—Ph 4-F—Ph 2762,4-diF—Ph 4-Cl—Ph 277 2,4-diF—Ph 4-NH2—Ph 278 2,4-diF—Ph 4-SO2NH2—Ph279 2,4-diF—Ph 4-CF3—Ph 280 2,4-diF—Ph 4-OCH3—Ph 281 2,4-diF—Ph 4-OEt—Ph282 2,4-diF—Ph 4-OCF3—Ph 283 2,4-diF—Ph 4-SO2CH3—Ph 284 2,4-diF—Ph4-OH—Ph 285 2,4-diF—Ph 4-CH3—Ph 286 2,4-diF—Ph 4-C2H5—Ph 287 2,4-diF—Ph2,4-diF—Ph 288 2,4-diF—Ph 2,5-diF—Ph 289 2,4-diF—Ph 3,4-dip—Ph 2902,4-diF—Ph 3,5-diF—Ph 291 2,4-diF—Ph 2,4-diCl—Ph 292 2,4-diF—Ph2,5-diCl—Ph 293 2,4-diF—Ph 3,4-diCl—Ph 294 2,4-diF—Ph 3,5-diCl—Ph 2952,4-diF—Ph 3,4-OCH2O—Ph 296 2,4-diF—Ph 3,4-OCH2CH2O—Ph 297 2,4-diF—Ph2-thienyl 298 2,4-diF—Ph 2-furanyl 299 2,4-diF—Ph 2-pyridyl 3002,4-diF—Ph 4-pyridyl 301 2,4-diF—Ph 2-imidazolyl 302 2,4-diF—Ph3-pyrazolyl 303 2,4-diF—Ph 2-thiazolyl 304 2,4-diF—Ph 5-tetrazolyl 3052,4-diF—Ph 1-adamantyl 306 4-Cl—Ph Ph 307 4-Cl—Ph 3-CN—Ph 308 4-Cl—Ph3-COCH3—Ph 309 4-Cl—Ph 3-CO2Me—Ph 310 4-Cl—Ph 3-CO2Et—Ph 311 4-Cl—Ph3-CO2H—Ph 312 4-Cl—Ph 3-CONH2—Ph 313 4-Cl—Ph 3-CONHMe—Ph 314 4-Cl—Ph3-F—Ph 315 4-Cl—Ph 3-Cl—Ph 316 4-Cl—Ph 3-Br—Ph 317 4-Cl—Ph 3-NO2—Ph 3184-Cl—Ph 3-NH2—Ph 319 4-Cl—Ph 3-NHMe—Ph 320 4-Cl—Ph 3-NMe2—Ph 321 4-Cl—Ph3-NHCOCH3—Ph 322 4-Cl—Ph 3-SO2NH2—Ph 323 4-Cl—Ph 3-SO2NHMe—Ph 3244-Cl—Ph 3-CF3—Ph 325 4-Cl—Ph 3-OCH3—Ph 326 4-Cl—Ph 3-OPh—Ph 327 4-Cl—Ph3-OCF3—Ph 328 4-Cl—Ph 3-SCH3—Ph 329 4-Cl—Ph 3-SOCH3—Ph 330 4-Cl—Ph3-SO2CH3—Ph 331 4-Cl—Ph 3-OH—Ph 332 4-Cl—Ph 3-CH2OH—Ph 333 4-Cl—Ph3-CHOHCH3—Ph 334 4-Cl—Ph 3-COH(CH3)2—Ph 335 4-Cl—Ph 3-CHOHPh—Ph 3364-Cl—Ph 3-CH3—Ph 337 4-Cl—Ph 3-C2H5—Ph 338 4-Cl—Ph 3-iPr-Ph 339 4-Cl—Ph3-tBu-Ph 340 4-Cl—Ph 3-Ph—Ph 341 4-Cl—Ph 3-CH2Ph—Ph 342 4-Cl—Ph3-CH2CO2Me—Ph 343 4-Cl—Ph 3-(1-piperidinyl)-Ph 344 4-Cl—Ph3-(1-pyrrolidinyl)-Ph 345 4-Cl—Ph 3-(2-imidazolyl)-Ph 346 4-Cl—Ph3-(1-imidazolyl)-Ph 347 4-Cl—Ph 3-(2-thiazolyl)-Ph 348 4-Cl—Ph3-(3-pyrazolyl)-Ph 349 4-Cl—Ph 3-(1-pyrazolyl)-Ph 350 4-Cl—Ph3-(1-tetrazolyl)-Ph 351 4-Cl—Ph 3-(5-tetrazolyl)-Ph 352 4-Cl—Ph3-(2-pyridyl)-Ph 353 4-Cl—Ph 3-(2-thienyl)-Ph 354 4-Cl—Ph3-(2-furanyl)-Ph 355 4-Cl—Ph 4-CN—Ph 356 4-Cl—Ph 4-COCH3—Ph 357 4-Cl—Ph4-CO2Me—Ph 358 4-Cl—Ph 4-CO2Et—Ph 359 4-Cl—Ph 4-CO2H—Ph 360 4-Cl—Ph4-CONH2—Ph 361 4-Cl—Ph 4-CONHMe—Ph 362 4-Cl—Ph 4-CONHPh—Ph 363 4-Cl—Ph4-NHCONH2—Ph 364 4-Cl—Ph 4-F—Ph 365 4-Cl—Ph 4-Cl—Ph 366 4-Cl—Ph 4-Br—Ph367 4-Cl—Ph 4-NO2—Ph 368 4-Cl—Ph 4-NH2—Ph 369 4-Cl—Ph 4-NHMe—Ph 3704-Cl—Ph 4-NMe2—Ph 371 4-Cl—Ph 4-NHCOCH3—Ph 372 4-Cl—Ph 4-SO2NH2—Ph 3734-Cl—Ph 4-SO2NHMe—Ph 374 4-Cl—Ph 4-CF3—Ph 375 4-Cl—Ph 4-OCH3—Ph 3764-Cl—Ph 4-OPh—Ph 377 4-Cl—Ph 4-OCF3—Ph 378 4-Cl—Ph 4-SCH3—Ph 379 4-Cl—Ph4-SOCH3—Ph 380 4-Cl—Ph 4-SO2CH3—Ph 381 4-Cl—Ph 4-OH—Ph 382 4-Cl—Ph4-CH2OH—Ph 383 4-Cl—Ph 4-CHOHCH3—Ph 384 4-Cl—Ph 4-COH(CH3)2—Ph 3854-Cl—Ph 4-CH3—Ph 386 4-Cl—Ph 4-C2H5—Ph 387 4-Cl—Ph 4-iPr-Ph 388 4-Cl—Ph4-tBu-Ph 389 4-Cl—Ph 4-Ph—Ph 390 4-Cl—Ph 4-CH2Ph—Ph 391 4-Cl—Ph4-CH2CO2Me—Ph 392 4-Cl—Ph 4-(1-piperidinyl)-Ph 393 4-Cl—Ph4-(1-pyrrolidinyl)-Ph 394 4-Cl—Ph 4-(2-imidazolyl)-Ph 395 4-Cl—Ph4-(1-imidazolyl)-Ph 396 4-Cl—Ph 4-(2-thiazolyl)-Ph 397 4-Cl—Ph4-(3-pyrazolyl)-Ph 398 4-Cl—Ph 4-(1-pyrazolyl)-Ph 399 4-Cl—Ph4-(1-tetrazolyl)-Ph 400 4-Cl—Ph 4-(5-tetrazolyl)-Ph 401 4-Cl—Ph4-(2-pyridyl)-Ph 402 4-Cl—Ph 4-(2-thienyl)-Ph 403 4-Cl—Ph4-(2-furanyl)-Ph 404 4-Cl—Ph 2-CN—Ph 405 4-Cl—Ph 2-COCH3—Ph 406 4-Cl—Ph2-CO2Me—Ph 407 4-Cl—Ph 2-CO2Et—Ph 408 4-Cl—Ph 2-CO2H—Ph 409 4-Cl—Ph2-CONH2—Ph 410 4-Cl—Ph 2-CONHMe—Ph 411 4-Cl—Ph 2-F—Ph 412 4-Cl—Ph2-Cl—Ph 413 4-Cl—Ph 2-Br—Ph 414 4-Cl—Ph 2-NO2—Ph 415 4-Cl—Ph 2-NH2—Ph416 4-Cl—Ph 2-NHMe—Ph 417 4-Cl—Ph 2-NMe2—Ph 418 4-Cl—Ph 2-NHCOCH3—Ph 4194-Cl—Ph 2-SO2NH2—Ph 420 4-Cl—Ph 2-SO2NHMe—Ph 421 4-Cl—Ph 2-CF3—Ph 4224-Cl—Ph 2-OCH3—Ph 423 4-Cl—Ph 2-OPh—Ph 424 4-Cl—Ph 2-OCF3—Ph 425 4-Cl—Ph2-SCH3—Ph 426 4-Cl—Ph 2-SOCH3—Ph 427 4-Cl—Ph 2-SO2CH3—Ph 428 4-Cl—Ph2-OH—Ph 429 4-Cl—Ph 2-CH2OH—Ph 430 4-Cl—Ph 2-CHOHCH3—Ph 431 4-Cl—Ph2-COH(CH3)2—Ph 432 4-Cl—Ph 2-CHOHPh—Ph 433 4-Cl—Ph 2-CH3—Ph 434 4-Cl—Ph2-C2H5—Ph 435 4-Cl—Ph 2-iPr-Ph 436 4-Cl—Ph 2-tBu-Ph 437 4-Cl—Ph 2-Ph—Ph438 4-Cl—Ph 2-CH2Ph—Ph 439 4-Cl—Ph 2-CH2CO2Me—Ph 440 4-Cl—Ph2-(1-piperidinyl)-Ph 441 4-Cl—Ph 2-(1-pyrrolidinyl)-Ph 442 4-Cl—Ph2-(2-imidazolyl)-Ph 443 4-Cl—Ph 2-(1-imidazolyl)-Ph 444 4-Cl—Ph2-(2-thiazolyl)-Ph 445 4-Cl—Ph 2-(3-pyrazolyl)-Ph 446 4-Cl—Ph2-(1-pyrazolyl)-Ph 447 4-Cl—Ph 2-(1-tetrazolyl)-Ph 448 4-Cl—Ph2-(5-tetrazolyl)-Ph 449 4-Cl—Ph 2-(2-pyridyl)-Ph 450 4-Cl—Ph2-(2-thienyl)-Ph 451 4-Cl—Ph 2-(2-furanyl)-Ph 452 4-Cl—Ph 2,4-diF—Ph 4534-Cl—Ph 2,5-diF—Ph 454 4-Cl—Ph 2,6-diF—Ph 455 4-Cl—Ph 3,4-diF—Ph 4564-Cl—Ph 3,5-diF—Ph 457 4-Cl—Ph 2,4-diCl—Ph 458 4-Cl—Ph 2,5-diCl—Ph 4594-Cl—Ph 2,6-diCl—Ph 460 4-Cl—Ph 3,4-diCl—Ph 461 4-Cl—Ph 3,5-diCl—Ph 4624-Cl—Ph 3,4-diCF3—Ph 463 4-Cl—Ph 3,5-diCF3—Ph 464 4-Cl—Ph 5-Cl-2-MeO—Ph465 4-Cl—Ph 5-Cl-2-Me—Ph 466 4-Cl—Ph 2-F-5-Me—Ph 467 4-Cl—Ph2-F-5-NO2—Ph 468 4-Cl—Ph 3,4-OCH2O—Ph 469 4-Cl—Ph 3,4-OCH2CH2O—Ph 4704-Cl—Ph 2-MeO-4-Me—Ph 471 4-Cl—Ph 2-MeO-5-Me—Ph 472 4-Cl—Ph 1-naphthyl473 4-Cl—Ph 2-naphthyl 474 4-Cl—Ph 2-thienyl 475 4-Cl—Ph 3-thienyl 4764-Cl—Ph 2-furanyl 477 4-Cl—Ph 3-furanyl 478 4-Cl—Ph 2-pyridyl 4794-Cl—Ph 3-pyridyl 480 4-Cl—Ph 4-pyridyl 481 4-Cl—Ph 2-indolyl 4824-Cl—Ph 3-indolyl 483 4-Cl—Ph 5-indolyl 484 4-Cl—Ph 6-indolyl 4854-Cl—Ph 3-indazolyl 486 4-Cl—Ph 5-indazolyl 487 4-Cl—Ph 6-indazolyl 4884-Cl—Ph 2-imidazolyl 489 4-Cl—Ph 3-pyrazolyl 490 4-Cl—Ph 2-thiazolyl 4914-Cl—Ph 5-tetrazolyl 492 4-Cl—Ph 2-benzimidazolyl 493 4-Cl—Ph5-benzimidazolyl 494 4-Cl—Ph 2-benzothiazolyl 495 4-Cl—Ph5-benzothiazolyl 496 4-Cl—Ph 2-benzoxazolyl 497 4-Cl—Ph 5-benzoxazolyl498 4-Cl—Ph 1-adamantyl 499 4-Cl—Ph 2-adamantyl 500 4-Cl—Ph t-Bu 5012-Cl—Ph 3-CN—Ph 502 2-Cl—Ph 3-COCH3—Ph 503 2-Cl—Ph 3-CO2Me—Ph 5042-Cl—Ph 3-CO2Et—Ph 505 2-Cl—Ph 3-CO2H—Ph 506 2-Cl—Ph 3-CONH2—Ph 5072-Cl—Ph 3-F—Ph 508 2-Cl—Ph 3-Cl—Ph 509 2-Cl—Ph 3-NH2—Ph 510 2-Cl—Ph3-SO2NH2—Ph 511 2-Cl—Ph 3-CF3—Ph 512 2-Cl—Ph 3-OCH3—Ph 513 2-Cl—Ph3-OEt—Ph 514 2-Cl—Ph 3-OCF3—Ph 515 2-Cl—Ph 3-SO2CH3—Ph 516 2-Cl—Ph3-OH—Ph 517 2-Cl—Ph 3-CH3—Ph 518 2-Cl—Ph 3-C2H5—Ph 519 2-Cl—Ph 4-CN—Ph520 2-Cl—Ph 4-COCH3—Ph 521 2-Cl—Ph 4-CO2Me—Ph 522 2-Cl—Ph 4-CO2Et—Ph 5232-Cl—Ph 4-CO2H—Ph 524 2-Cl—Ph 4-CONH2—Ph 525 2-Cl—Ph 4-F—Ph 526 2-Cl—Ph4-Cl—Ph 527 2-Cl—Ph 4-NH2—Ph 528 2-Cl—Ph 4-SO2NH2—Ph 529 2-Cl—Ph4-CF3—Ph 530 2-Cl—Ph 4-OCH3—Ph 531 2-Cl—Ph 4-OEt—Ph 532 2-Cl—Ph4-OCF3—Ph 533 2-Cl—Ph 4-SO2CH3—Ph 534 2-Cl—Ph 4-OH—Ph 535 2-Cl—Ph4-CH3—Ph 536 2-Cl—Ph 4-C2H5—Ph 537 2-Cl—Ph 2,4-diF—Ph 538 2-Cl—Ph2,5-diF—Ph 539 2-Cl—Ph 3,4-diF—Ph 540 2-Cl—Ph 3,5-diF—Ph 541 2-Cl—Ph2,4-diCl—Ph 542 2-Cl—Ph 2,5-diCl—Ph 543 2-Cl—Ph 3,4-diCl—Ph 544 2-Cl—Ph3,5-diCl—Ph 545 2-Cl—Ph 3,4-OCH2O—Ph 546 2-Cl—Ph 3,4-OCH2CH2O—Ph 5472-Cl—Ph 2-thienyl 548 2-Cl—Ph 2-furanyl 549 2-Cl—Ph 2-pyridyl 5502-Cl—Ph 4-pyridyl 551 2-Cl—Ph 2-imidazolyl 552 2-Cl—Ph 3-pyrazolyl 5532-Cl—Ph 2-thiazolyl 554 2-Cl—Ph 5-tetrazolyl 555 2-Cl—Ph 1-adamantyl 5562,4-diCl—Ph 3-CN—Ph 557 2,4-diCl—Ph 3-COCH3—Ph 558 2,4-diCl—Ph3-CO2Me—Ph 559 2,4-diCl—Ph 3-CO2Et—Ph 560 2,4-diCl—Ph 3-CO2H—Ph 5612,4-diCl—Ph 3-CONH2—Ph 562 2,4-diCl—Ph 3-F—Ph 563 2,4-diCl—Ph 3-Cl—Ph564 2,4-diCl—Ph 3-NH2—Ph 565 2,4-diCl—Ph 3-SO2NH2—Ph 566 2,4-diCl—Ph3-CF3—Ph 567 2,4-diCl—Ph 3-OCH3—Ph 568 2,4-diCl—Ph 3-OEt—Ph 5692,4-diCl—Ph 3-OCF3—Ph 570 2,4-diCl—Ph 3-SO2CH3—Ph 571 2,4-diCl—Ph3-OH—Ph 572 2,4-diCl—Ph 3-CH3—Ph 573 2,4-diCl—Ph 3-C2H5—Ph 5742,4-diCl—Ph 4-CN—Ph 575 2,4-diCl—Ph 4-COCH3—Ph 576 2,4-diCl—Ph4-CO2Me—Ph 577 2,4-diCl—Ph 4-CO2Et—Ph 578 2,4-diCl—Ph 4-CO2H—Ph 5792,4-diCl—Ph 4-CONH2—Ph 580 2,4-diCl—Ph 4-F—Ph 581 2,4-diCl—Ph 4-Cl—Ph582 2,4-diCl—Ph 4-NH2—Ph 583 2,4-diCl—Ph 4-SO2NH2—Ph 584 2,4-diCl—Ph4-CF3—Ph 585 2,4-diCl—Ph 4-OCH3—Ph 586 2,4-diCl—Ph 4-OEt—Ph 5872,4-diCl—Ph 4-OCF3—Ph 588 2,4-diCl—Ph 4-SO2CH3—Ph 589 2,4-diCl—Ph4-OH—Ph 590 2,4-diCl—Ph 4-CH3—Ph 591 2,4-diCl—Ph 4-C2H5—Ph 5922,4-diCl—Ph 2,4-diF—Ph 593 2,4-diCl—Ph 2,5-diF—Ph 594 2,4-diCl—Ph3,4-diF—Ph 595 2,4-diCl—Ph 3,5-diF—Ph 596 2,4-diCl—Ph 2,4-diCl—Ph 5972,4-diCl—Ph 2,5-diCl—Ph 598 2,4-diCl—Ph 3,4-diCl—Ph 599 2,4-diCl—Ph3,5-diCl—Ph 600 2,4-diCl—Ph 3,4-OCH2O—Ph 601 2,4-diCl—Ph 3,4-OCH2CH2O—Ph602 2,4-diCl—Ph 2-thienyl 603 2,4-diCl—Ph 2-furanyl 604 2,4-diCl—Ph2-pyridyl 605 2,4-diCl—Ph 4-pyridyl 606 2,4-diCl—Ph 2-imidazolyl 6072,4-diCl—Ph 3-pyrazolyl 608 2,4-diCl—Ph 2-thiazolyl 609 2,4-diCl—Ph5-tetrazolyl 610 2,4-diCl—Ph 1-adamantyl 611 3-OCH3—Ph 3-CN—Ph 6123-OCH3—Ph 3-COCH3—Ph 613 3-OCH3—Ph 3-CO2Me—Ph 614 3-OCH3—Ph 3-CO2Et—Ph615 3-OCH3—Ph 3-CO2H—Ph 616 3-OCH3—Ph 3-CONH2—Ph 617 3-OCH3—Ph 3-F—Ph618 3-OCH3—Ph 3-Cl—Ph 619 3-OCH3—Ph 3-NH2—Ph 620 3-OCH3—Ph 3-SO2NH2—Ph621 3-OCH3—Ph 3-CF3—Ph 622 3-OCH3—Ph 3-OCH3—Ph 623 3-OCH3—Ph 3-OEt—Ph624 3-OCH3—Ph 3-OCF3—Ph 625 3-OCH3—Ph 3-SO2CH3—Ph 626 3-OCH3—Ph 3-OH—Ph627 3-OCH3—Ph 3-CH3—Ph 628 3-OCH3—Ph 3-C2H5—Ph 629 3-OCH3—Ph 4-CN—Ph 6303-OCH3—Ph 4-COCH3—Ph 631 3-OCH3—Ph 4-CO2Me—Ph 632 3-OCH3—Ph 4-CO2Et—Ph633 3-OCH3—Ph 4-CO2H—Ph 634 3-OCH3—Ph 4-CONH2—Ph 635 3-OCH3—Ph 4-F—Ph636 3-OCH3—Ph 4-Cl—Ph 637 3-OCH3—Ph 4-NH2—Ph 638 3-OCH3—Ph 4-SO2NH2—Ph639 3-OCH3—Ph 4-CF3—Ph 640 3-OCH3—Ph 4-OCH3—Ph 641 3-OCH3—Ph 4-OEt—Ph642 3-OCH3—Ph 4-OCF3—Ph 643 3-OCH3—Ph 4-SO2CH3—Ph 644 3-OCH3—Ph 4-OH—Ph645 3-OCH3—Ph 4-CH3—Ph 646 3-OCH3—Ph 4-C2H5—Ph 647 3-OCH3—Ph 2,4-diF—Ph648 3-OCH3—Ph 2,5-diF—Ph 649 3-OCH3—Ph 3,4-diF—Ph 650 3-OCH3—Ph3,5-diF—Ph 651 3-OCH3—Ph 2,4-diCl—Ph 652 3-OCH3—Ph 2,5-diCl—Ph 6533-OCH3—Ph 3,4-diCl—Ph 654 3-OCH3—Ph 3,5-diCl—Ph 655 3-OCH3—Ph3,4-OCH2O—Ph 656 3-OCH3—Ph 3,4-OCH2CH2O—Ph 657 3-OCH3—Ph 2-thienyl 6583-OCH3—Ph 2-furanyl 659 3-OCH3—Ph 2-pyridyl 660 3-OCH3—Ph 4-pyridyl 6613-OCH3—Ph 2-imidazolyl 662 3-OCH3—Ph 3-pyrazolyl 663 3-OCH3—Ph2-thiazolyl 664 3-OCH3—Ph 5-tetrazolyl 665 3-OCH3—Ph 1-adamantyl 6662-thienyl 3-CN—Ph 667 2-thienyl 3-COCH3—Ph 668 2-thienyl 3-F—Ph 6692-thienyl 3-Cl—Ph 670 2-thienyl 3-NH2—Ph 671 2-thienyl 3-OCH3—Ph 6722-thienyl 3-OH—Ph 673 2-thienyl 4-CN—Ph 674 2-thienyl 4-COCH3—Ph 6752-thienyl 4-F—Ph 676 2-thienyl 4-Cl—Ph 677 2-thienyl 4-NH2—Ph 6782-thienyl 4-OCH3—Ph 679 2-thienyl 4-OH—Ph 680 2-thienyl 3,4-diF—Ph 6812-thienyl 3,5-diF—Ph 682 2-thienyl 3,4-diCl—Ph 683 2-thienyl 3,5-diCl—Ph684 2-thienyl 3,4-OCH2O—Ph 685 2-thienyl 3,4-OCH2CH2O—Ph 686 3-thienyl3-CN—Ph 687 3-thienyl 3-COCH3—Ph 688 3-thienyl 3-F—Ph 689 3-thienyl3-Cl—Ph 690 3-thienyl 3-NH2—Ph 691 3-thienyl 3-OCH3—Ph 692 3-thienyl3-OH-Ph 693 3-thienyl 4-CN—Ph 694 3-thienyl 4-COCH3—Ph 695 3-thienyl4-F—Ph 696 3-thienyl 4-Cl—Ph 697 3-thienyl 4-NH2—Ph 698 3-thienyl4-OCH3—Ph 699 3-thienyl 4-OH—Ph 700 3-thienyl 3,4-diF—Ph 701 3-thienyl3,5-diF—Ph 702 3-thienyl 3,4-diCl—Ph 703 3-thienyl 3,5-diCl—Ph 7043-thienyl 3,4-OCH2O—Ph 705 3-thienyl 3,4-OCH2CH2O—Ph 706 2-furanyl3-CN—Ph 707 2-furanyl 3-COCH3—Ph 708 2-furanyl 3-F—Ph 709 2-furanyl3-Cl—Ph 710 2-furanyl 3-NH2—Ph 711 2-furanyl 3-OCH3—Ph 712 2-furanyl3-OH—Ph 713 2-furanyl 4-CN—Ph 714 2-furanyl 4-COCH3—Ph 715 2-furanyl4-F—Ph 716 2-furanyl 4-Cl—Ph 717 2-furanyl 4-NH2—Ph 718 2-furanyl4-OCH3—Ph 719 2-furanyl 4-OH—Ph 720 2-furanyl 3,4-diF—Ph 721 2-furanyl3,5-diF—Ph 722 2-furanyl 3,4-diCl—Ph 723 2-furanyl 3,5-diCl—Ph 7242-furanyl 3,4-OCH2O—Ph 725 2-furanyl 3,4-OCH2CH2O—Ph 726 3-furanyl3-CN—Ph 727 3-furanyl 3-COCH3—Ph 728 3-furanyl 3-F—Ph 729 3-furanyl3-Cl—Ph 730 3-furanyl 3-NH2—Ph 731 3-furanyl 3-OCH3—Ph 732 3-furanyl3-OH—Ph 733 3-furanyl 4-CN—Ph 734 3-furanyl 4-COCH3—Ph 735 3-furanyl4-F—Ph 736 3-furanyl 4-Cl—Ph 737 3-furanyl 4-NH2—Ph 738 3-furanyl4-OCH3—Ph 739 3-furanyl 4-OH—Ph 740 3-furanyl 3,4-diF—Ph 741 3-furanyl3,5-diF—Ph 742 3-furanyl 3,4-diCl—Ph 743 3-furanyl 3,5-diCl—Ph 7443-furanyl 3,4-OCH2O—Ph 745 3-furanyl 3,4-OCH2CH2O—Ph 746 2-pyridyl3-CN—Ph 747 2-pyridyl 3-COCH3—Ph 748 2-pyridyl 3-F—Ph 749 2-pyridyl3-Cl—Ph 750 2-pyridyl 3-NH2—Ph 751 2-pyridyl 3-OCH3—Ph 752 2-pyridyl3-OH—Ph 753 2-pyridyl 4-CN—Ph 754 2-pyridyl 4-COCH3—Ph 755 2-pyridyl4-F—Ph 756 2-pyridyl 4-Cl—Ph 757 2-pyridyl 4-NH2—Ph 758 2-pyridyl4-OCH3—Ph 759 2-pyridyl 4-OH—Ph 760 2-pyridyl 3,4-diF—Ph 761 2-pyridyl3,5-diF—Ph 762 2-pyridyl 3,4-diCl—Ph 763 2-pyridyl 3,5-diCl—Ph 7642-pyridyl 3,4-OCH2O—Ph 765 2-pyridyl 3,4-OCH2CH2O—Ph 766 3-pyridyl3-CN—Ph 767 3-pyridyl 3-COCH3—Ph 768 3-pyridyl 3-F—Ph 769 3-pyridyl3-Cl—Ph 770 3-pyridyl 3-NH2—Ph 771 3-pyridyl 3-OCH3—Ph 772 3-pyridyl3-OH—Ph 773 3-pyridyl 4-CN—Ph 774 3-pyridyl 4-COCH3—Ph 775 3-pyridyl4-F—Ph 776 3-pyridyl 4-Cl—Ph 777 3-pyridyl 4-NH2—Ph 778 3-pyridyl4-OCH3—Ph 779 3-pyridyl 4-OH—Ph 780 3-pyridyl 3,4-diF—Ph 781 3-pyridyl3,5-diF—Ph 782 3-pyridyl 3,4-diCl—Ph 783 3-pyridyl 3,5-diCl—Ph 7843-pyridyl 3,4-OCH2O—Ph 785 3-pyridyl 3,4-OCH2CH2O—Ph 786 4-pyridyl3-CN—Ph 787 4-pyridyl 3-COCH3—Ph 788 4-pyridyl 3-F—Ph 789 4-pyridyl3-Cl—Ph 790 4-pyridyl 3-NH2—Ph 791 4-pyridyl 3-OCH3—Ph 792 4-pyridyl3-OH—Ph 793 4-pyridyl 4-CN—Ph 794 4-pyridyl 4-COCH3—Ph 795 4-pyridyl4-F—Ph 796 4-pyridyl 4-Cl—Ph 797 4-pyridyl 4-NH2—Ph 798 4-pyridyl4-OCH3—Ph 799 4-pyridyl 4-OH—Ph 800 4-pyridyl 3,4-diF—Ph 801 4-pyridyl3,5-diF—Ph 802 4-pyridyl 3,4-diCl—Ph 803 4-pyridyl 3,5-diCl—Ph 8044-pyridyl 3,4-OCH2O—Ph 805 4-pyridyl 3,4-OCH2CH2O—Ph 806 3-indolyl3-CN—Ph 807 3-indolyl 3-COCH3—Ph 808 3-indolyl 3-F—Ph 809 3-indolyl3-Cl—Ph 810 3-indolyl 3-NH2—Ph 811 3-indolyl 3-OCH3—Ph 812 3-indolyl3-OH—Ph 813 3-indolyl 4-CN—Ph 814 3-indolyl 4-COCH3—Ph 815 3-indolyl4-F—Ph 816 3-indolyl 4-Cl—Ph 817 3-indolyl 4-NH2—Ph 818 3-indolyl4-OCH3—Ph 819 3-indolyl 4-OH—Ph 820 3-indolyl 3,4-diF—Ph 821 3-indolyl3,5-diF—Ph 822 3-indolyl 3,4-diCl—Ph 823 3-indolyl 3,5-diCl—Ph 8243-indolyl 3,4-OCH2O—Ph 825 3-indolyl 3,4-OCH2CH2O—Ph 826 5-indolyl3-CN—Ph 827 5-indolyl 3-COCH3—Ph 828 5-indolyl 3-F—Ph 829 5-indolyl3-Cl—Ph 830 5-indolyl 3-NH2—Ph 831 5-indolyl 3-OCH3—Ph 832 5-indolyl3-OH—Ph 833 5-indolyl 4-CN—Ph 834 5-indolyl 4-COCH3—Ph 835 5-indolyl4-F—Ph 836 5-indolyl 4-Cl—Ph 837 5-indolyl 4-NH2—Ph 838 5-indolyl4-OCH3—Ph 839 5-indolyl 4-OH—Ph 840 5-indolyl 3,4-diF—Ph 841 5-indolyl3,5-diF—Ph 842 5-indolyl 3,4-diCl—Ph 843 5-indolyl 3,5-diCl—Ph 8445-indolyl 3,4-OCH2O—Ph 845 5-indolyl 3,4-OCH2CH2O—Ph 846 5-indazolyl3-CN—Ph 847 5-indazolyl 3-COCH3—Ph 848 5-indazolyl 3-F—Ph 8495-indazolyl 3-Cl—Ph 850 5-indazolyl 3-NH2—Ph 851 5-indazolyl 3-OCH3—Ph852 5-indazolyl 3-OH—Ph 853 5-indazolyl 4-CN—Ph 854 5-indazolyl4-COCH3—Ph 855 5-indazolyl 4-F—Ph 856 5-indazolyl 4-Cl—Ph 8575-indazolyl 4-NH2—Ph 858 5-indazolyl 4-OCH3—Ph 859 5-indazolyl 4-OH—Ph860 5-indazolyl 3,4-diF—Ph 861 5-indazolyl 3,5-diF—Ph 862 5-indazolyl3,4-diCl—Ph 863 5-indazolyl 3,5-diCl—Ph 864 5-indazolyl 3,4-OCH2O—Ph 8655-indazolyl 3,4-OCH2CH2O—Ph 866 5-benzimidazolyl 3-CN—Ph 8675-benzimidazolyl 3-COCH3—Ph 868 5-benzimidazolyl 3-F—Ph 8695-benzimidazolyl 3-Cl—Ph 870 5-benzimidazolyl 3-NH2—Ph 8715-benzimidazolyl 3-OCH3—Ph 872 5-benzimidazolyl 3-OH—Ph 8735-benzimidazolyl 4-CN—Ph 874 5-benzimidazolyl 4-COCH3—Ph 8755-benzimidazolyl 4-F—Ph 876 5-benzimidazolyl 4-Cl—Ph 8775-benzimidazolyl 4-NH2—Ph 878 5-benzimidazolyl 4-OCH3—Ph 8795-benzimidazolyl 4-OH—Ph 880 5-benzimidazolyl 3,4-diF—Ph 8815-benzimidazolyl 3,5-diF—Ph 882 5-benzimidazolyl 3,4-diCl—Ph 8835-benzimidazolyl 3,5-diCl—Ph 884 5-benzimidazolyl 3,4-OCH2O—Ph 8855-benzimidazolyl 3,4-OCH2CH2O—Ph 886 5-benzothiazolyl 3-CN—Ph 8875-benzothiazolyl 3-COCH3—Ph 888 5-benzothiazolyl 3-F—Ph 8895-benzothiazolyl 3-Cl—Ph 890 5-benzothiazolyl 3-NH2—Ph 8915-benzothiazolyl 3-OCH3—Ph 892 5-benzothiazolyl 3-OH—Ph 8935-benzothiazolyl 4-CN—Ph 894 5-benzothiazolyl 4-COCH3—Ph 8955-benzothiazolyl 4-F—Ph 896 5-benzothiazolyl 4-Cl—Ph 8975-benzothiazolyl 4-NH2—Ph 898 5-benzothiazolyl 4-OCH3—Ph 8995-benzothiazolyl 4-OH—Ph 900 5-benzothiazolyl 3,4-diF—Ph 9015-benzothiazolyl 3,5-diF—Ph 902 5-benzothiazolyl 3,4-diCl—Ph 9035-benzothiazolyl 3,5-diCl—Ph 904 5-benzothiazolyl 3,4-OCH2O—Ph 9055-benzothiazolyl 3,4-OCH2CH2O—Ph 906 5-benzoxazolyl 3-CN—Ph 9075-benzoxazolyl 3-COCH3—Ph 908 5-benzoxazolyl 3-F—Ph 909 5-benzoxazolyl3-Cl—Ph 910 5-benzoxazolyl 3-NH2—Ph 911 5-benzoxazolyl 3-OCH3—Ph 9125-benzoxazolyl 3-OH—Ph 913 5-benzoxazolyl 4-CN—Ph 914 5-benzoxazolyl4-COCH3—Ph 915 5-benzoxazolyl 4-F—Ph 916 5-benzoxazolyl 4-Cl—Ph 9175-benzoxazolyl 4-NH2—Ph 918 5-benzoxazolyl 4-OCH3—Ph 919 5-benzoxazolyl4-OH—Ph 920 5-benzoxazolyl 3,4-diF—Ph 921 5-benzoxazolyl 3,5-diF—Ph 9225-benzoxazolyl 3,4-diCl—Ph 923 5-benzoxazolyl 3,5-diCl—Ph 9245-benzoxazolyl 3,4-OCH2O—Ph 925 5-benzoxazolyl 3,4-OCH2CH2O—Ph

Utility

The utility of the compounds in accordance with the present invention asmodulators of chemokine receptor activity may be demonstrated bymethodology known in the art, such as the assays for CCR-2 and CCR-3ligand binding, as disclosed by Ponath et al., J. Exp. Med., 183,2437-2448 (1996) and Uguccioni et al., J. Clin. Invest., 100, 1137-1143(1997). Cell lines for expressing the receptor of interest include thosenaturally expressing the chemokine receptor, such as EOL-3 or THP-1,those induced to express the chemokine receptor by the addition ofchemical or protein agents, such as HL-60 or AML14.3D10 cells treatedwith, for example, butyric acid with interleukin-S present, or a cellengineered to express a recombinant chemokine receptor, such as CHO orHEK-293. Finally, blood or tissue cells, for example human peripheralblood eosinophils, isolated using methods as described by Hansel et al.,J. Immunol. Methods, 145, 105-110 (1991), can be utilized in suchassays. In particular, the compound of the present invention haveactivity in binding to the CCR-3 receptor in the aforementioned assays.As used herein, “activity” is intended to mean a compound demonstratingan IC50 of 10 μM or lower in concentration when measured in theaforementioned assays. Such a result is indicative of the intrinsicactivity of the compounds as modulators of chemokine receptor activity.A general binding protocol is described below.

CCR3-Receptor Binding Protocol

Millipore filter plates (#MABVN1250) are treated with 5 μg/ml protaminein phosphate buffered saline, pH 7.2, for ten minutes at roomtemperature. Plates are washed three times with phosphate bufferedsaline and incubated with phosphate buffered saline for thirty minutesat room temperature. For binding, 50 μl of binding buffer (0.5% bovineserum albumen, 20 mM HEPES buffer and 5 mM magnesium chloride in RPMI1640 media) with or without a test concentration of a compound presentat a known concentration is combined with 50 μl of 125-I labeled humaneotaxin (to give a final concentration of 150 pM radioligand) and 50 μlof cell suspension in binding buffer containing 5×10⁵ total cells. Cellsused for such binding assays can include cell lines transfected with agene expressing CCR3 such as that described by Daugherty et al. (1996),isolated human eosinophils such as described by Hansel et al. (1991) orthe AML14.3D10 cell line after differentiation with butyric acid asdescribed by Tiffany et al. (1998). The mixture of compound, cells andradioligand are incubated at room temperature for thirty minutes. Platesare placed onto a vacuum manifold, vacuum applied, and plates washedthree times with binding buffer with 0.5M NaCl added. The plastic skirtis removed from the plate, the plate allowed to air dry, the wells punchout and CPM counted. The percent inhibition of binding is calculatedusing the total count obtained in the absence of any competing compoundor chemokine ligand and the background binding determined by addition of100 nM eotaxin in place of the test compound.

The utility of the compounds in accordance with the present invention asinhibitors of the migration of eosinophils or cell lines expressing thechemokine receptors may be demonstrated-by methodology known in the art,such as the chemotaxis assay disclosed by Bacon et al., Brit. J.Pharmacol., 95, 966-974 (1988). In particular, the compound of thepresent invention have activity in inhibition of the migration ofeosinophils in the aforementioned assays. As used herein, “activity” isintended to mean a compound demonstrating an IC50 of 10 μM or lower inconcentration when measured in the aforementioned assays. Such a resultis indicative of the intrinsic activity of the compounds as modulatorsof chemokine receptor activity. A human eosinophil chemotaxis assayprotocol is described below.

Human Eosinophil Chemotaxis Assay

Neuroprobe MBA96 96-well chemotaxis chambers with Neuroprobepolyvinylpyrrolidone-free polycarbonate PFD5 5-micron filters in placeare warmed in a 37° C. incubator prior to assay. Freshly isolated humaneosinophils, isolated according to a method such as that described byHansel et al. (1991), are suspended in RPMI 1640 with 0.1% bovine serumalbumin at 1×10⁶ cells/ml and warmed in a 37° C. incubator prior toassay. A 20 nM solution of human eotaxin in RPMI 1640 with 0.1% bovineserum albumin is warmed in a 37° C. incubator prior to assay. Theeosinophil suspension and the 20 nM eotaxin solution are each mixed 1:1with prewarmed RPMI 1640 with 0.1% bovine serum albumin with or withouta dilution of a test compound that is at two fold the desired finalconcentration. These mixtures are warmed in a 37° C. incubator prior toassay. The filter is separated from the prewarmed Neuroprobe chemotaxischamber and the eotaxin/compound mixture is placed into a PolyfiltronicsMPC 96 well plate that has been placed in the bottom part of the NeuroProbe chemotaxis chamber. The approximate volume is 370 microliters andthere should be a positive meniscus after dispensing. The filter isreplaced above the 96 well plate, the rubber gasket is attached to thebottom of the upper chamber, and the chamber assembled. A 200 μl volumeof the cell suspension/compound mixture is added to the appropriatewells of the upper chamber. The upper chamber is covered with a platesealer, and the assembled unit placed in a 37° C. incubator for 45minutes. After incubation, the plate sealer is removed and all remainingcell suspension is aspirated off. The chamber is disassembled and, whileholding the filter by the sides at a 90-degree angle, unmigrated cellsare washed away using a gentle stream of phosphate buffered salinedispensed from a squirt bottle and then the filter wiped with a rubbertipped squeegee. The filter is allowed to completely dry and immersedcompletely in Wright Giemsa stain for 30-45 seconds. The filter isrinsed with distilled water for 7 minutes, rinsed once with waterbriefly, and allowed to dry. Migrated cells are enumerated bymicroscopy.

Mammalian chemokine receptors provide a target for interfering with orpromoting immune cell function in a mammal, such as a human. Compoundsthat inhibit or promote chemokine receptor function are particularlyuseful for modulating immune cell function for therapeutic purposes.Accordingly, the present invention is directed to compounds which areuseful in the prevention and/or treatment of a wide variety ofinflammatory, infectious, and immunoregulatory disorders and diseases,including asthma and allergic diseases, infection by pathogenic microbes(which, by definition, includes viruses), as well as autoimmunepathologies such as the rheumatoid arthritis and atherosclerosis.

For example, an instant compound which inhibits one or more functions ofa mammalian chemokine receptor (e.g., a human chemokine receptor) may beadministered to inhibit (i.e., reduce or prevent) inflammation orinfectious disease. As a result, one or more inflammatory process, suchas leukocyte emigration, adhesion, chemotaxis, exocytosis (e.g., ofenzymes, histamine) or inflammatory mediator release, is inhibited. Forexample, eosinophilic infiltration to inflammatory sites (e.g., inasthma or allergic rhinitis) can be inhibited according to the presentmethod. In particular, the compound of the following examples hasactivity in blocking the migration of cells expressing the CCR-3receptor using the appropriate chemokines in the aforementioned assays.As used herein, “activity” is intended to mean a compound demonstratingan IC50 of 10 μM or lower in concentration when measured in theaforementioned assays. Such a result is also indicative of the intrinsicactivity of the compounds as modulators of chemokine receptor activity.

Similarly, an instant compound which promotes one or more functions ofthe mammalian chemokine receptor (e.g., a human chemokine) asadministered to stimulate (induce or enhance) an immune or inflammatoryresponse, such as leukocyte emigration, adhesion, chemotaxis, exocytosis(e.g., of enzymes, histamine) or inflammatory mediator release,resulting in the beneficial stimulation of inflammatory processes. Forexample, eosinophils can be recruited to combat parasitic infections. Inaddition, treatment of the aforementioned inflammatory, allergic andautoimmune diseases can also be contemplated for an instant compoundwhich promotes one or more functions of the mammalian chemokine receptorif one contemplates the delivery of sufficient compound to cause theloss of receptor expression on cells through the induction of chemokinereceptor internalization or the delivery of compound in a manner thatresults in the misdirection of the migration of cells.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals, including but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species.The subject treated in the methods above is a mammal, male or female, inwhom modulation of chemokine receptor activity is desired. “Modulation”as used herein is intended to encompass antagonism, agonism, partialantagonism and/or partial agonism.

Diseases or conditions of human or other species which can be treatedwith inhibitors of chemokine receptor function, include, but are notlimited to: inflammatory or allergic diseases and conditions, includingrespiratory allergic diseases such as asthma, allergic rhinitis,hypersensitivity lung diseases, hypersensitivity pneumonitis,eosinophilic cellulitis (e.g., Well's syndrome), eosinophilic pneumonias(e.g., Loeffler's syndrome, chronic eosinophilic pneumonia),eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-typehypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathicpulmonary fibrosis, or ILD associated with rheumatoid arthritis,systemic lupus erythematosus, ankylosing spondylitis, systemicsclerosis, Sjogren's syndrome, polymyositis or dermatomyositis);systemic anaphylaxis or hypersensitivity responses, drug allergies(e.g., to penicillin, cephalosporins), eosinophilia-myalgia syndrome dueto the ingestion of contaminated tryptophan, insect sting allergies;autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis,multiple sclerosis, systemic lupus erythematosus, myasthenia gravis,juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis,Behcet's disease; graft rejection (e.g., in transplantation), includingallograft rejection or graft-versus-host disease; inflammatory boweldiseases, such as Crohn's disease and ulcerative colitis;spondyloarthropathies; scleroderma; psoriasis (including T-cell mediatedpsoriasis) and inflammatory dermatoses such as an dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis(e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);eosinophilic myositis, eosinophilic fasciitis; cancers with leukocyteinfiltration of the skin or organs. Other diseases or conditions inwhich undesirable inflammatory responses are to be inhibited can betreated, including, but not limited to, reperfusion injury,atherosclerosis, certain hematologic malignancies, cytokine-inducedtoxicity (e.g., septic shock, endotoxic shock), polymyositis,dermatomyositis. Infectious diseases or conditions of human or otherspecies which can be treated with inhibitors of chemokine receptorfunction, include, but are not limited to, HIV.

Diseases or conditions of humans or other species which can be treatedwith promoters of chemokine receptor function, include, but are notlimited to: immunosuppression, such as that in individuals withimmunodeficiency syndromes such as AIDS or other viral infections,individuals undergoing radiation therapy, chemotherapy, therapy forautoimmune disease or drug therapy (e.g., corticosteroid therapy), whichcauses immunosuppression; immunosuppression due to congenital deficiencyin receptor function or other causes; and infections diseases, such asparasitic diseases, including, but not limited to helminth infections,such as nematodes (round worms); (Trichuriasis, Enterobiasis,Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis);trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tapeworms) (Echinococcosis, Taeniasis saginata, Cysticercosis); visceralworms, visceral larva migraines (e.g., Toxocara), eosinophilicgastroenteritis (e.g., Anisaki sp., Phocanema sp.), cutaneous larvamigraines (Ancylostona braziliense, Ancylostoma caninum). The compoundsof the present invention are accordingly useful in the prevention andtreatment of a wide variety of inflammatory, infectious andimmunoregulatory disorders and diseases. In addition, treatment of theaforementioned inflammatory, allergic and autoimmune diseases can alsobe contemplated for promoters of chemokine receptor function if onecontemplates the delivery of sufficient compound to cause the loss ofreceptor expression on cells through the induction of chemokine receptorinternalization or delivery of compound in a manner that results in themisdirection of the migration of cells.

In another aspect, the instant invention may be used to evaluate theputative specific agonists or antagonists of a G protein coupledreceptor. The present invention is directed to the use of thesecompounds in the preparation and execution of screening assays forcompounds that modulate the activity of chemokine receptors.Furthermore, the compounds of this invention are useful in establishingor determining the binding site of other compounds to chemokinereceptors, e.g., by competitive inhibition or as a reference in an assayto compare its known activity to a compound with an unknown activity.When developing new assays or protocols, compounds according to thepresent invention could be used to test their effectiveness.Specifically, such compounds may be provided in a commercial kit, forexample, for use in pharmaceutical research involving the aforementioneddiseases. The compounds of the instant invention are also useful for theevaluation of putative specific modulators of the chemokine receptors.In addition, one could utilize compounds of this invention to examinethe specificity of G protein coupled receptors that are not thought tobe chemokine receptors, either by serving as examples of compounds whichdo not bind or as structural variants of compounds active on thesereceptors which may help define specific sites of interaction.

Combined therapy to prevent and treat inflammatory, infectious andimmunoregulatory disorders and diseases, including asthma and allergicdiseases, as well as autoimmune pathologies such as rheumatoid arthritisand atherosclerosis, and those pathologies noted above is illustrated bythe combination of the compounds of this invention and other compoundswhich are known for such utilities. For example, in the treatment orprevention of inflammation, the present compounds may be used inconjunction with an anti-inflammatory or analgesic agent such as anopiate agonist, a lipoxygenase inhibitor, a cyclooxygenase-2 inhibitor,an interleukin inhibitor, such as an interleukin-1 inhibitor, a tumornecrosis factor inhibitor, an NMDA antagonist, an inhibitor or nitricoxide or an inhibitor of the synthesis of nitric oxide, a non-steroidalanti-inflammatory agent, a phosphodiesterase inhibitor, or acytokine-suppressing anti-inflammatory agent, for example with acompound such as acetaminophen, aspirin, codeine, fentaynl, ibuprofen,indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, asteroidal analgesic, sufentanyl, sunlindac, interferon alpha and thelike. Similarly, the instant compounds may be administered with a painreliever; a potentiator such as caffeine, an H2-antagonist, simethicone,aluminum or magnesium hydroxide; a decongestant such as phenylephrine,phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine,naphazoline, xylometazoline, propylhexedrine, or levodesoxy-ephedrine;and antitussive such as codeine, hydrocodone, caramiphen,carbetapentane, or dextramethorphan; a diuretic; and a sedating ornon-sedating antihistamine. Likewise, compounds of the present inventionmay be used in combination with other drugs that are used in thetreatment/prevention/suppression or amelioration of the diseases orconditions for which compound of the present invention are useful. Suchother drugs may be administered, by a route and in an amount commonlyused therefore, contemporaneously or sequentially with a compound of thepresent invention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is preferred. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention. Examples of other active ingredients that may becombined with a compound of the present invention, either administeredseparately or in the same pharmaceutical compositions, include, but arenot limited to: (a) integrin antagonists such as those for selectins,ICAMs and VLA-4; (b) steroids such as beclomethasone,methylprednisolone, betamethasone, prednisone, dexamethasone, andhydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus,rapamycin and other FK-506 type immunosuppressants; (d) antihistamines(H1-histamine antagonists) such as bromopheniramine, chlorpheniramine,dexchlorpheniramine, triprolidine, clemastine, diphenhydramine,diphenylpyraline, tripelennamine, hydroxyzine, methdilazine,promethazine, trimeprazine, azatadine, cyproheptadine, antazoline,pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine,fexofenadine, descarboethoxyloratadine, and the like; (e) non-steroidalanti-asthmatics such as b2-agonists (terbutaline, metaproterenol,fenoterol, isoetharine, albuteral, bitolterol, and pirbuterol),theophylline, cromolyn sodium, atropine, ipratropium bromide,leukotriene antagonists (zafirlukast, montelukast, pranlukast,iralukast, pobilukast, SKB-102,203), leukotriene biosynthesis inhibitors(zileuton, BAY-1005); (f) non-steroidal antiinflammatory agents (NSAIDs)such as propionic acid derivatives (alminoprofen, benxaprofen, bucloxicacid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin,pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen),acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, andzomepirac), fenamic acid derivatives (flufenamic acid, meclofenamicacid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams(isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetylsalicylic acid, sulfasalazine) and the pyrazolones (apazone,bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone);(g) cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitors ofphosphodiesterase type IV (PDE-IV); (I) other antagonists of thechemokine receptors; (j) cholesterol lowering agents such as HMG-COAreductase inhibitors (lovastatin, simvastatin and pravastatin,fluvastatin, atorvsatatin, and other statins), sequestrants(cholestyramine and colestipol), nicotonic acid, fenofibric acidderivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), andprobucol; (k) anti-diabetic agents such as insulin, sulfonylureas,biguanides (metformin), a-glucosidase inhibitors (acarbose) andglitazones (troglitazone ad pioglitazone); (1) preparations ofinterferons (interferon alpha-2a, interferon-2B, interferon alpha-N3,interferon beta-1a, interferon beta-1b, interferon gamma-1b); (m)antiviral compounds such as efavirenz, nevirapine, indinavir,ganciclovir, lamivudine, famciclovir, and zalcitabine; (o) othercompound such as 5-aminosalicylic acid an prodrugs thereof,antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxiccancer chemotherapeutic agents. The weight ratio of the compound of thepresent invention to the second active ingredient may be varied and willdepend upon the effective doses of each ingredient. Generally, aneffective dose of each will be used. Thus, for example, when a compoundof the present invention is combined with an NSAID the weight ratio ofthe compound of the present invention to the NSAID will generally rangefrom about 1000:1 to about 1:1000, preferably about 200:1 to about1:200. Combinations of a compound of the present invention and otheractive ingredients will generally also be within the aforementionedrange, but in each case, an effective dose of each active ingredientshould be used.

The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of Formula I that, when administered alone or incombination with an additional therapeutic agent to a mammal, iseffective to prevent or ameliorate the thromboembolic disease conditionor the progression of the disease.

Dosage and Formulation

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient,and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will rangefrom about 1 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate; stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Representative useful pharmaceutical dosage-forms for administration ofthe compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 100 milligrams of active ingredient, 0.2 milligrams of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams ofmicrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution should be made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin.

Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 to100 milligrams of the compound of Formula I and about 1 to 7.5milligrams of the second anticoagulant, per kilogram of patient bodyweight. For a tablet dosage form, the compounds of this inventiongenerally may be present in an amount of about 5 to 10 milligrams perdosage unit, and the second anti-coagulant in an amount of about 1 to 5milligrams per dosage unit.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of Formula I and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial which effects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low-viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contract between thecomponents of combination products of the present invention, whetheradministered in a single dosage form or administered in separate formsbut at the same time by the same manner, will be readily apparent tothose skilled in the art, once armed with the present disclosure.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise that as specifically describedherein.

What is claimed is:
 1. A compound of formula (I):

or stereoisomers or pharmaceutically acceptable salts thereof, wherein:Q is selected from CH₂, CHR⁵, CHR¹³, CR¹³R¹³, and CR⁵R¹³; K, and L areindependently selected from CH₂, CHR⁵, CHR⁶, CR⁶R⁶ and CR⁵R⁶; with theproviso: at least one of J, K, L, or Q contains an R⁵; J is selectedfrom CH₂, CHR⁵, CHR¹³, and CR⁵R¹³; Z is selected from O and S; E isselected from:

ring A is phenyl or naphthyl; R¹ and R² are independently selected fromH, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, anda (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(a); R^(a),at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂, CN,(CH₂)_(r)NR^(b)R^(b), (CH₂)_(r)OH, (CH₂)_(r)OR^(c), (CH₂)_(r)SH,(CH₂)_(r)SR^(c), (CH₂)_(r)C(O)R^(b), (CH₂)_(r)C(O)NR^(b)R^(b),(CH₂)_(r)NR^(b)C(O)R^(b), (CH₂)_(r)C(O)OR^(b), (CH₂)_(r)OC(O)R^(c),(CH₂)_(r)CH(═NR^(b))NR^(b)R^(b), (CH₂)_(r)NHC(═NR^(b))NR^(b)R^(b),(CH₂)_(r)S(O)_(p)R^(c), (CH₂)_(r)S(O)₂NR^(b)R^(b),(CH₂)_(r)NR^(b)S(O)₂R^(c), and (CH₂)_(r)phenyl; R^(b), at eachoccurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl;R^(c), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl,and phenyl; alternatively; R² and R³ join to form a 5, 6, or 7-memberedring substituted with 0-3 R^(a); R³ is selected from a(CR³′R³″)_(r)—C₃₋₈ carbocyclic residue substituted with 1 R¹⁵′ and 0-4R¹⁵; a (CR³′R³″)_(r)—C₉₋₁₀ carbocyclic residue substituted with 0-4 R¹⁵;and a (CR³′R³″)_(r)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R¹⁵; R³′ andR³″, at each occurrence, are selected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, and phenyl; R⁴ is absent, taken with the nitrogen to whichit is attached to form an N-oxide, or selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(q)C(O)R^(4b),(CH₂)_(q)C(O)NR^(4a)R^(4a)′, (CH₂)_(q)C(O)OR^(4b), and a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(4c); R^(4a) and R^(4a)′, ateach occurrence, are selected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, and phenyl; R^(4b), at each occurrence, is selected fromC₁₋₆ alkyl, C₂₋₈ alkenyl, (CH₂)_(r)C₃₋₆ cycloalkyl, C₂₋₈ alkynyl, andphenyl; R^(4c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(4a)R^(4a)′, and (CH₂)_(r)phenyl; alternatively, R⁴ joinswith R⁷, R⁹, R¹¹, or R¹⁴ to form a 5, 6 or 7 membered piperidiniumspirocycle or pyrrolidinium spirocycle substituted with 0-3 R^(a); R⁵ isselected from a (CR⁵′R⁵″)_(t)-C₃₋₁₀ carbocyclic residue substituted with0-5 R¹⁶ and a (CR⁵′R⁵″)_(t)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R¹⁶; R⁵′and R⁵″, at each occurrence, are selected from H, C₁₋₆ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl; R⁶, at each occurrence, isselected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, (CF₂)_(r)CF₃, CN, (CH₂)_(r)NR^(6a)R^(6a)′, (CH₂)_(r)OH,(CH₂)_(r)OR^(6b), (CH₂)_(r)SH, (CH₂)_(r)SR^(6b), (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(6b), (CH₂)_(r)C(O)NR^(6a)R^(6a)′,(CH₂)_(r)NR^(6d)C(O)R^(6a), (CH₂)_(r)C(O)OR^(6b), (CH₂)_(r)OC(O)R^(6b),(CH₂)_(r)S(O)_(p)R^(6b), (CH₂)_(r)S(O)₂NR^(6a)R^(6a),(CH₂)_(r)NR^(6d)S(O)₂R^(6b), and (CH₂)_(t)phenyl substituted with 0-3R^(6c); R^(6a) and R^(6a)′, at each occurrence, are selected from H,C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(6c);R^(6b), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl substituted with 0-3 R^(6c); R^(6c), at eachoccurrence, is selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅alkyl, and (CH₂)_(r)NR^(6d)R^(6d); R^(6d), at each occurrence, isselected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; with the proviso thatwhen any of J, K, or L is CR⁶R⁶ and R⁶ is halogen, cyano, nitro, orbonded to the carbon to which it is attached through a heteroatom, theother R⁶ is not halogen, cyano, or bonded to the carbon to which it isattached through a heteroatom; R⁷, is selected from H, C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(q)OH, (CH₂)_(q)SH, (CH₂)_(q)OR^(7d),(CH₂)_(q)SR^(7d), (CH₂)_(q)NR^(7a)R^(7a)′, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(7b), (CH₂)_(r)C(O)NR^(7a)R^(7a)′,(CH₂)_(q)NR^(7a)C(O)R^(7a), (CH₂)_(q)NR^(7a)C(O)H, (CH₂)_(r)C(O)OR^(7b),(CH₂)_(q)OC(O)R^(7b), (CH₂)_(q)S(O)_(p)R^(7b),(CH₂)_(q)S(O)₂NR^(7a)R^(7a)′, (CH₂)_(q)NR^(7a)S(O)₂R^(7b), C₁₋₆haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3R^(7c), and a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(7c);R^(7a) and R^(7a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(7e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(7e); R^(7b), at each occurrence, isselected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)C₃₋₆carbocyclic residue substituted with 0-2 R^(7e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(7e); R^(7c), at each occurrence, isselected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(7f)R^(7f),(CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl,(CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(7b), (CH₂)_(r)C(O)NR^(7f)R^(7f),(CH₂)_(r)NR^(7f)C(O)R^(7a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,(CH₂)_(r)OC(O)R^(7b), (CH₂)_(r)C(═NR^(7f))NR^(7f)R^(7f),(CH₂)_(r)S(O)_(p)R^(7b), (CH₂)_(r)NHC(NR^(7f))NR^(7f)R^(7f),(CH₂)_(r)S(O)₂NR^(7f)R^(7f), (CH₂)_(r)NR^(7f)S(O)₂R^(7b), and(CH₂)_(r)phenyl substituted with 0-3 R^(7e); R^(7d), at each occurrence,is selected from C₁₋₆ alkyl substituted with 0-3 R^(7e), alkenyl,alkynyl, and a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7c);R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl; R^(7f), at each occurrence,is selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R⁸ is selected fromH, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(t)phenyl substituted with 0-3R^(8a); R^(8a), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl; alternatively, R⁷ and R⁸join to form C₃₋₇ cycloalkyl, or ═NR^(8b); R^(8b) is selected from H,C₁₋₆ alkyl, C₃₋₆ cycloalkyl, OH, CN, and (CH₂)_(r)-phenyl; R⁹, isselected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, F, Cl, Br, I,NO₂, CN, (CH₂)_(r)OH, (CH₂)_(r)SH, (CH₂)_(r)OR^(9d), (CH₂)_(r)SR^(9d),(CH₂)_(r)NR^(9a)R^(9a)′, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(9b),(CH₂)_(r)C(O)NR^(9a)R^(9a)′, (CH₂)_(r)NR^(9a)C(O)R^(9a),(CH₂)_(r)NR^(9a)C(O)H, (CH₂)_(r)NR^(9a)C(O)NHR^(9a),(CH₂)_(r)C(O)OR^(9b), (CH₂)_(r)OC(O)R^(9b), (CH₂)_(r)OC(O)NHR^(9a),(CH₂)_(r)S(O)_(p)R^(9b), (CH₂)_(r)S(O)₂NR^(9a)R^(9a)′,(CH₂)_(r)NR^(9a)S(O)₂R^(9b), C₁₋₆ haloalkyl, a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(9c), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(9c); R^(9a) and R^(9a)′, at eachoccurrence, are selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(9e), and a(CH₂)_(r)-5-10 menibered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(9e); R^(9b), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(9e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(9e); R^(9c), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂, CN,(CH₂)_(r)NR^(9f)R^(9f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(9b),(CH₂)_(r)C(O)NR^(9f)R^(9f), (CH₂)_(r)NR^(9f)C(O)R^(9a),(CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(9b),(CH₂)_(r)C(═NR^(9f))NR^(9f)R^(9f), (CH₂)_(r)S(O)_(p)R^(9b),(CH₂)_(r)NHC(═NR^(9f))NR^(9f)R^(9f), (CH₂)_(r)S(O)₂NR^(9f)R^(9f),(CH₂)_(r)NR^(9f)S(O)₂R^(9b), and (CH₂)_(r)phenyl substituted with 0-3R^(9e); R^(9d), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, a C₃₋₁₀ carbocyclic residue substituted with 0-3R^(9c), and a 5-6 membered heterocyclic system containing 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R^(9c); R^(9e), at each occurrence, is selectedfrom C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ Cycloalkyl,Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH,(CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(9f)R^(9f), and (CH₂)_(r)phenyl;R^(9f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl; R¹⁰, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, F, Cl, Br, I, NO₂, CN, (CH₂)_(r)OH, (CH₂)_(r)OR^(10d),(CH₂)_(r)SR^(10d), (CH₂)_(r)NR^(10a)R^(10a)′, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(10b), (CH₂)_(r)C(O)NR^(10a)R^(10a)′,(CH₂)_(r)NR^(10a)C(O)R^(10a), (CH₂)_(r)NR^(10a)C(O)H,(CH₂)_(r)C(O)OR^(10b), (CH₂)_(r)OC(O)R^(10b), (CH₂)_(r)S(O)_(p)R^(10b),(CH₂)_(r)S(O)₂NR^(10a)R^(10a), (CH₂)_(r)NR^(10a)S(O)₂R^(10b), C₁₋₆haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(10c), and a (CH₂)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(10c);R^(10a) and R^(10a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(10e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(10e); R^(10b), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)C₃₋₆ carbocyclic residuesubstituted with 0-2 R^(10e), and a (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(10e); R^(10c), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I,F, (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(10f)R^(10f)′, (CH₂)_(r)OH,(CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(10b), (CH₂)_(r)C(O)NR^(10f)R^(10f)′,(CH₂)_(r)NR^(10f)C(O)R^(10a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,(CH₂)_(r)OC(O)R^(10b), (CH₂)_(r)C(═NR^(10f))NR^(10f)R^(10f),(CH₂)_(r)S(O)_(p)R^(10b), (CH₂)_(r)NHC(═NR^(10f))NR^(10f)R^(10f),(CH₂)_(r)S(O)₂NR^(10f)R^(10f), (CH₂)_(r)NR^(10f)S(O)₂R^(10b), and(CH₂)_(r)phenyl substituted with 0-3 R^(10e); R^(10d), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aC₃₋₁₀ carbocyclic residue substituted with 0-3 R^(10c), and a 5-6membered heterocyclic system containing 1-4 heteroatoms selected fromthe group consisting of N, O, and S substituted with 0-3 R^(10c);R^(10e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(10f)R^(10f), and (CH₂)_(r)phenyl; R^(10f), at eachoccurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆ cycloalkyl;alternatively, R⁹ and R¹⁰ join to form C₃₋₇ cycloalkyl, 5-6-memberedcyclic ketal or ═O; with the proviso that when R¹⁰ is halogen, cyano,nitro, or bonded to the carbon to which it is attached through aheteroatom, R⁹ is not halogen, cyano, or bonded to the carbon to whichit is attached through a heteroatom; R¹¹, is selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(q)OH, (CH₂)_(q)SH,(CH₂)_(q)OR^(11d), (CH₂)_(q)SR^(11d), (CH₂)_(q)NR^(11a)R^(11a)′,(CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(11b), (CH₂)_(r)C(O)NR^(11a)R^(11a)′,(CH₂)_(q)NR^(11a)C(O)R^(11a), (CH₂)_(q)NR^(11a)C(O)NHR^(11a),(CH₂)_(r)C(O)OR^(11b), (CH₂)_(q)OC(O)R^(11b), (CH₂)_(q)S(O)_(p)R^(11b),(CH₂)_(q)S(O)₂NR^(11a)R^(11a)′, (CH₂)_(q)NR^(11a)S(O)₂R^(11b), C₁₋₆haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(11c), and a (CH₂)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(11c);R^(11a) and R^(11a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(11e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(11e); R^(11b), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-2 R^(11e), and a (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(11e); R^(11c), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I,F, (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(11f)R^(11f), (CH₂)_(r)OH,(CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(11b), (CH₂)_(r)C(O)NR^(11f)R^(11f),(CH₂)_(r)NR^(11f)C(O)R^(11a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,(CH₂)_(r)OC(O)R^(11b), (CH₂)_(r)C(═NR^(11f)R^(11f),(CH₂)_(r)NHC(═NR^(11f))NR^(11f)R^(11f), (CH₂)_(r)S(O)_(p)R^(11b),(CH₂)_(r)S(O)₂NR^(11f)R^(11f), (CH₂)_(r)NR^(11f)S(O)₂R^(11b), and(CH₂)_(r)phenyl substituted with 0-3 R^(11e); R^(11d), at eachoccurrence, is selected from C₁₋₆ alkyl substituted with 0-3 R^(11e),C₂₋₆ alkenyl, C₂₋₆ alkynyl, and a C₃₋₁₀ carbocyclic residue substitutedwith 0-3 R^(11c); R^(11e), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl; R^(11f), at eachoccurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R¹² isselected from H, C₁₋₆ alkyl, (CH₂)_(q)OH, (CH₂)_(r)C₃₋₆ cycloalkyl, and(CH₂)tphenyl substituted with 0-3 R^(12a); R^(12a), at each occurrence,is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(9f)R^(9f), and(CH₂)_(r)phenyl; alternatively, R¹¹ and R¹² join to form C₃₋₇cycloalkyl; R¹³, at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, (CF₂)_(w)CF₃,(CH₂)_(r)NR^(13a)R^(13a)′, (CH₂)_(r)OH, (CH₂)_(r)OR^(13b), (CH₂)_(r)SH,(CH₂)_(r)SR^(13b), (CH₂)_(w)C(O)OH, (CH₂)_(w)C(O)R^(13b),(CH₂)_(w)C(O)NR^(13a)R^(13a)′, (CH₂)_(r)NR^(13d)C(O)R^(13a),(CH₂)_(w)C(O)OR^(13b), (CH₂)_(r)OC(O)R^(13b), (CH₂)_(w)S(O)_(p)R^(13b),(CH₂)_(w)S(O)₂NR^(13a)R^(13a)′, (CH₂)_(r)R^(13d)S(O)₂R^(13b), and(CH₂)_(w)-phenyl substituted with 0-3 R^(13c); R^(13a) and R^(13a)′, ateach occurrence, are selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, andphenyl substituted with 0-3 R^(13c); R^(13b), at each occurrence, isselected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with0-3 R^(13c); R^(13c), at each occurrence, is selected from C₁₋₆ alkyl,C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl, and (CH₂)_(r)NR^(13d)R^(13d);R^(13d), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl; R¹⁴, at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(14a)R^(14a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(14d),(CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(14d), (CHR′)_(r)C(O) OH, (CHR′)_(r)C(O)(CHR′)_(r)R^(14b), (CHR′)_(r)C(O)NR^(14a)R^(14a)′,(CHR′)_(r)NR^(14f)C(O)(CHR′)_(r)R^(14b),(CHR′)_(r)C(O)O(CHR′)_(r)R^(14d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(14b),(CHR′)_(r)C(═NR^(14f))NR^(14a)R^(14a)′,(CHR′)_(r)NHC(═NR^(14f))NR^(14f)R^(14f),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(14b), (CHR′)_(r)S(O)₂NR^(14a)R^(14a)′,(CHR′)_(r)NR^(14f)S(O)₂(CHR′)_(r)R^(4b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(14e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e), or two R¹⁴ substituents onadjacent atoms on ring A form to join a 5-6 membered heterocyclic systemcontaining 1-3 heteroatoms selected from N, O, and S substituted with0-2 R^(15e); alternatively, R¹⁴ joins with R⁴ to form a 5, 6 or 7membered piperidinium spirocycle or pyrrolidinium spirocycle fused toring A, the spirocycle substituted with 0-3 R^(a); R′, at eachoccurrence, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with R^(14e);R^(14a) and R^(14a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(14e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(14e); R^(14b), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-3 R^(14e), and (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(14e); R^(14d), at each occurrence, is selected from C₂₋₈alkenyl, C₂₋₈ alkynyl, C₁₋₆ alkyl substituted with 0-3 R^(14e), a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(14e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(14e); R^(14e), ateach occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(14f)R^(14f), and (CH₂)_(r)phenyl; R^(14f), at eachoccurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl;R¹⁵, at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(15a)R^(15a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(15d),(CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(15d),(CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)C(O)NR^(15a)R^(15a)′, (CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),(CHR′)_(r)C(═NR^(15f))NR^(15a)R^(15a)′,(CHR′)_(r)NHC(═NR^(15f))NR^(15f)R^(15f),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)₂NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R¹⁵′, at each occurrence, isselected from C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,(CHR′)_(r)NR^(15a)R^(15a)′, (CHR′)_(r)O(CHR′)_(r)R^(15d), (CHR′)_(r)SH,(CHR′)₃₋₅C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(15d), (CHR′)_(q)C(O)OH,(CHR′)_(q)C(O)(CHR′)_(q)R^(15b), (CHR′)_(r)C(O)NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),(CHR′)_(r)C(═NR^(15f))NR^(15a)R^(15a)′,(CHR′)_(r)NHC(═NR^(15f))NR^(15f)R^(15f),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)₂NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₂₋₈ alkenyl substituted with0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, (CHR′)_(r)phenylsubstituted with 0-3 R^(15e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(15e); R^(15a) and R^(15a)′, at each occurrence, are selectedfrom H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(5e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R^(15b), at each occurrence, isselected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆carbocyclic residue substituted with 0-3 R^(15e), and (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R^(15d), at each occurrence, isselected from C₂₋₈ alkenyl, C₂₋₈ a alkynyl, C₁₋₆ alkyl substituted with0-3 R^(15e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3R^(15e), and a (CH₂)_(r)5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(15e);R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(15f)R^(15f), and (CH₂)_(r)phenyl; R^(15f), at eachoccurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl;R¹⁶, at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(16a)R^(16a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(16d),(CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(16d),(CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)C(O)NR^(16a)R^(16a)′, (CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)C(O)O(CHR′)_(r)R^(16d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(16b),(CHR′)_(r)C(═NR^(16f))NR^(16a)R^(16a)′,(CHR′)_(r)NHC(═NR^(16f))NR^(16f)R^(16f),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂NR^(16a)R^(16a)′,(CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and(CHR′)_(r)phenyl substituted with 0-3 R^(16e); R^(16a) and R^(16a)′, ateach occurrence, are selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(16e), and a (CH₂)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(16e);R^(16b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3R^(16e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(16e);R^(16d), at each occurrence, is selected from C₂₋₈ alkenyl, C₂₋₈alkynyl, C₁₋₆ alkyl substituted with 0-3 R^(16e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(16e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(16e); R^(16e), at each occurrence, isselected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(16f)R^(16f), and(CH₂)_(r)phenyl; R^(16f), at each occurrence, is selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl, and phenyl; g is selected from 0, 1, 2, 3,and 4; t is selected from 1 and 2; w is selected from 0 and 1; r isselected from 0, 1, 2, 3, 4, and 5; q is selected from 1, 2, 3, 4, and5; and p is selected from 0, 1, 2, and
 3. 2. The compound of claim 1,wherein: Z is selected from O and S; E is selected from:

R⁴ is absent, taken with the nitrogen to which it is attached to form anN-oxide, or selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and(CH₂)_(r)-phenyl substituted with 0-3 R^(4c); R^(4c), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(4a)R^(4a)′, and(CH₂)_(r)phenyl; alternatively, R⁴ joins with R⁷ R⁹, or R¹⁴ to form a 5,6 or 7 membered piperidinium spirocycle substituted with 0-3 R^(a); R¹and R² are independently selected from H and C₁₋₄ alkyl; R⁶, at eachoccurrence, is selected from C₁₋₄ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, (CF₂)_(r)CF₃, CN, (CH₂)_(r)OH,(CH₂)_(r)OH^(6b), (CH₂)_(r)C(O)R^(6b), (CH₂)_(r)C(O)NR^(6a)R^(6a)′,(CH₂)_(r)NR^(6d)C(O)R^(6a), and (CH₂)_(t)phenyl substituted with 0-3R^(6c); R^(6a) and R^(6a)′, at each occurrence, are selected from H,C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(6c);R^(6b), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl substituted with 0-3 R^(6c); R^(6c), at eachoccurrence, is selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅alkyl, and (CH₂)_(r)NR^(6d)R^(6d); R^(6d), at each occurrence, isselected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R⁷, is selected fromH, C₁₋₃ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(q)OH, (CH₂)_(q)OR^(7d),(CH₂)_(q)NR^(7a)R^(7a)′, (CH₂)_(r)C(O)R^(7b),(CH₂)_(r)C(O)NR^(7a)R^(7a)′, (CH₂)_(q)NR^(7a)C(O)R^(7a), C₁₋₆ haloalkyl,(CH₂)_(r)phenyl with 0-2 R^(7c); R^(7a) and R^(7a)′, at each occurrence,are selected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a(CH₂)_(r)phenyl substituted with 0-3 R^(7e); R^(7b), at each occurrence,is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, (CH₂)_(r)phenyl substituted with 0-3 R^(7e); R^(7c), at eachoccurrence, is selected from C₁₋₄ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂, CN,(CH₂)_(r)NR^(7f)R^(7f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)C(O)R^(7b), (CH₂)_(r)C(O)NR^(7f)R^(7f),(CH₂)_(r)NR^(7f)C(O)R^(7a), (CH₂)_(r)S(O)_(p)R^(7b),(CH₂)_(r)S(O)₂NR^(7f)R^(7f), (CH₂)_(r)NR^(7f)S(O)₂R^(7b), and(CH₂)_(r)phenyl substituted with 0-2 R^(7e); R^(7d), at each occurrence,is selected from C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(r)phenylsubstituted with 0-3 R^(7e); R^(7e), at each occurrence, is selectedfrom C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br,I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅alkyl, (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl; R^(7f), at eachoccurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆ cycloalkyl; p1 R⁸is H or joins with R⁷ to form C₃₋₇ cycloalkyl or ═NR^(8b); R¹¹, isselected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(q)OH,(CH₂)_(q)OR^(11d), (CH₂)_(q)NR^(11a)R^(11a)′, (CH₂)_(r)C(O)R^(11b),(CH₂)_(r)C(O)NR^(11a)R^(11a)′, (CH₂)_(q)NR^(11a)C(O)R^(11a), C₁₋₆haloalkyl, (CH₂)_(r)phenyl with 0-2 R^(11c), (CH₂)_(r)-5-10 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R¹⁵; R^(11a) and R^(11a)′, at each occurrence,are selected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a(CH₂)_(r)phenyl substituted with 0-3 R^(11e); R^(11b), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(r)phenyl substituted with 0-3 R^(11e);R^(11c), at each occurrence, is selected from C₁₋₄ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(11f)R^(11f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)C(O)R^(11b), (CH₂)_(r)C(O)NR^(11f)R^(11f),(CH₂)_(r)NR^(11f)C(O)R^(11a), (CH₂)_(r)S(O)_(p)R^(11b),(CH₂)_(r)S(O)₂NR^(11f)R^(11f), (CH₂)_(r)NR^(11f)S(O)₂R^(11b), and(CH₂)_(r)phenyl substituted with 0-2 R^(11e); R^(11d), at eachoccurrence, is selected from c₁₋₆ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl,(CH₂)_(r)phenyl substituted with 0-3 R^(11e); R^(11e), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(11f)R^(11f), and(CH₂)_(r)phenyl; R^(11f), at each occurrence, is selected from H, C₁₋₅alkyl and C₃₋₆ cycloalkyl; R¹² is H or joins with R¹¹ to form C₃₋₇cycloalkyl; R¹³, at each occurrence, is selected from C₁₋₄ alkyl, C₃₋₆cycloalkyl, (CH₂)NR^(13a)R^(13a)′, (CH₂)OH, (CH₂)OR^(13b, (CH)₂)_(w)C(O)R^(13b), (CH₂)_(w)C(O)NR^(13a)R^(13a)′,(CH₂)NR^(13d)C(O)R^(13a), (CH₂)_(w)S(O)₂NR^(13a)R^(13a)′,(CH₂)NR^(13d)S(O)₂R^(13b), and (CH₂)_(w)-phenyl substituted with 0-3R^(13c); R^(13a) and R^(13a)′, at each occurrence, are selected from H,C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(13c);R^(13b), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl substituted with 0-3 R^(13c); R^(13c), at eachoccurrence, is selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, and(CH₂)_(r)NR^(13d)R^(13d); R^(13d), at each occurrence, is selected fromH, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; q is selected from 1, 2, and 3; andr is selected from 0, 1, 2, and
 3. 3. The compound of claim 2, wherein:ring A is selected from:

R³ is selected from a (CR³′H)_(r)—C₃₋₈ carbocyclic residue substitutedwith 1 R¹⁵′ and 0-4 R¹⁵, wherein the C₃₋₈ carbocyclic residue isselected from phenyl, C₃₋₆ cycloalkyl; a (CR₃′H)_(r)—C₉₋₁₀ carbocyclicresidue substituted with 0-4 R¹⁵, wherein the C₉₋₁₀ carbocyclic residueis selected from naphthyl and adamantyl; and a (CR³′H)_(r)-heterocyclicsystem substituted with 0-3 R¹⁵, wherein the heterocyclic system isselected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl,benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl,benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl,indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl,pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl,thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and R⁵ is selected from(CR⁵′H)_(t)-phenyl substituted with 0-5 R¹⁶; and a(CR₅′H)_(t)-heterocyclic system substituted with 0-3 R¹⁶, wherein theheterocyclic system is selected from pyridinyl, thiophenyl, furanyl,indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl,imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl,1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl.
 4. The compound of claim 3, wherein formula(I) is:

with the proviso that at least one of K or L contains an R⁵; R¹⁶, ateach occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl,CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(16a)R^(16a)′, NO₂, CN, OH,(CH₂)_(r)OR^(16d), (CH₂)_(r)C(O)R^(16b), (CH₂)_(r)C(O)NR^(16a)R^(16a)′,(CH₂)_(r)NR^(16f)C(O)R^(16b), (CH₂)_(r)S(O)_(p)R^(16b),(CH₂)_(r)S(O)₂NR^(16a)R^(16a)′, (CH₂)_(r)NR^(16f)S(O)₂R^(16b), and(CH₂)_(r)phenyl substituted with 0-3 R^(16e); R^(16a) and R^(16a)′, ateach occurrence, are selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with 0-3 R^(16e); R^(16b), at eachoccurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with 0-3 R^(16e); R^(16d), at eachoccurrence, is selected from C₁₋₆ alkyl and phenyl; R^(16e), at eachoccurrence, is selected from C₂₋₆ alkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and R^(16f), at eachoccurrence, is selected from H, and C₁₋₅ alkyl.
 5. The compound of claim4, wherein: R⁵ is CH₂phenyl substituted with 0-3 R¹⁶; R⁹, is selectedfrom H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, F, Cl, CN, (CH₂)_(r)OH,(CH₂)_(r)OR^(9d), (CH₂)_(r)NR^(9a)R^(9a′), (CH₂)_(r)OC(O)NHR^(9a),(CH₂)_(r)phenyl substituted with 0-5 R^(9e), and a heterocyclic systemsubstituted with 0-2 R^(9e), wherein the heterocyclic system is selectedfrom pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl; R^(9a) andR⁹′, at each occurrence, are selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(9e); R^(9d), ateach occurrence, is selected from C₁₋₆ alkyl and phenyl; R^(9e), at eachoccurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; R¹⁰ is selected from H, C₁₋₈alkyl, OH, and CH₂OH; alternatively, R⁹ and R¹⁰ join to form C₃₋₇cycloalkyl, 5-6-membered cyclic ketal or ═O; with the proviso that whenR¹⁰ is halogen, cyano, nitro, or bonded to the carbon to which it isattached through a heteroatom, R⁹ is not halogen, cyano, or bonded tothe carbon to which it is attached through a heteroatom; R¹¹ is selectedfrom H, C₁₋₈ alkyl, (CH₂)_(r)phenyl substituted with 0-5 R^(11e), and a(CH₂)_(r)-heterocyclic system substituted with 0-2 R^(11e), wherein theheterocyclic system is selected from pyridinyl, thiophenyl, furanyl,indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl,imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl,1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl; and R^(11e), at each occurrence, is selectedfrom C₁₋₆ alkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, OH, and(CH₂)_(r)OC₁₋₅ alkyl; R¹² is H; alternatively, R¹¹ and R¹² join to formC₃₋₇ cycloalkyl; R¹⁴, at each occurrence, is selected from C₁₋₈ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(14a)R^(14a)′,NO₂, CN, OH, (CH₂)_(r)OR^(14d), (CH₂)_(r)C(O)R^(14b),(CH₂)_(r)C(O)NR^(14a)R^(14a)′, (CH₂)_(r)NR^(14f)C(O)R^(14b),(CH₂)_(r)S(O)_(p)R^(14b), (CH₂)_(r)S(O)₂NR^(14a)R^(14a)′,(CH₂)_(r)NR^(14f)S(O)₂R^(14b), (CH₂)_(r)phenyl substituted with 0-3R^(14e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e), ortwo R¹⁴ substituents on adjacent atoms on ring A form to join a 5-6membered heterocyclic system containing 1-3 heteroatoms selected from N,O, and S substituted with 0-2 R^(15e); R^(14a) and R^(14a)′, at eachoccurrence, are selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with 0-3 R^(14e); R^(14b), at eachoccurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with 0-3 R^(14e); R^(14d), at eachoccurrence, is selected from C₁₋₆ alkyl and phenyl; R^(14e), at eachoccurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; R^(14f), at each occurrence,is selected from H, and C₁₋₅ alkyl; and r is selected from 0, 1, and 2.6. The compound of claim 5, wherein: L is selected from CH₂ and CHR⁵; R³is selected from a C₃₋₈ carbocyclic residue substituted with 1 R¹⁵′ and0-3 R¹⁵, wherein the C₃₋₈ carbocyclic residue is selected fromcyclopropyl, cyclopentyl, cyclohexyl, and phenyl; a C₉₋₁₀ carbocyclicresidue substituted with 0-3 R¹⁵, wherein the C₉₋₁₀ carbocyclic residueis selected from naphthyl and adamantyl; and a (CR₃′H)_(r)-heterocyclicsystem substituted with 0-3 R¹⁵, wherein the heterocyclic system isselected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl,benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl,benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl,indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl,pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl,thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and R¹⁵, at eachoccurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, CF₃,Cl, Br, I, F, (CH₂)_(r)NR^(15a)R^(15a)′, NO₂, CN, OH, (CH₂)_(r)OR^(15d),(CH₂)_(r)C(O)R^(15b), (CH₂)_(r)C(O)NR^(15a)R^(15a)′,(CH₂)_(r)NR^(15f)C(O)R^(15b), (CH₂)_(r)S(O)_(p)R^(15b),(CH₂)_(r)S(O)₂NR^(15a)R^(15a)′, (CH₂)_(r)NR^(15f)S(O)₂R^(15b), and(CH₂)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R^(15a) and R^(15a)′, at eachoccurrence, are selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with 0-3 R^(15e); R^(15b), at eachoccurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with 0-3 R^(15e); R^(15d), at eachoccurrence, is selected from C₁₋₆ alkyl and phenyl; R^(15e), at eachoccurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and R^(15f), at eachoccurrence, is selected from H and C₁₋₅ alkyl.
 7. A pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim
 6. 8. A methodfor modulation of chemokine receptor activity comprising administeringto a patient in need thereof a therapeutically effective amount of acompound of claim
 6. 9. A method for treating inflammatory diseases,comprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound of claim
 6. 10. A method for treatingasthma, comprising administering to a patient in need thereof atherapeutically effective amount of a compound of claim
 6. 11. A methodfor treating disorders comprising administering to a patient in needthereof a therapeutically effective amount of a compound of claim 6,wherein the disorder is selected from asthma, allergic rhinitis, atopicdermatitis, inflammatory bowel diseases, idiopathic pulmonary fibrosis,bullous pemphigoid, helminthic parasitic infections, allergic colitis,eczema, conjunctivitis, transplantation, familial eosinophilia,eosinophilic cellulitis, eosinophilic pneumonias, eosinophilicfasciitis, eosinophilic gastroenteritis, drug induced eosinophilia, HIVinfection, cystic fibrosis, Churg-Strauss syndrome, lymphoma, Hodgkin'sdisease, and colonic carcinoma.
 12. The method of claim 11 for treatingdisorders selected from asthma, allergic rhinitis, atopic dermatitis,and inflammatory bowel diseases.
 13. A pharmaceutical composition,comprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of a compound of claim
 1. 14. A method for modulationof chetnokine receptor activity comprising administering to a patient inneed thereof a therapeutically effective amount of a compound ofclaim
 1. 15. A method for treating inflammatory diseases, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of claim
 1. 16. A method for treating asthma,comprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound of claim
 1. 17. A method for modulationof chemokine receptor activity comprising administering to a patient inneed thereof a therapeutically effective amount of a compound ofclaim
 1. 18. A method for modulation of chemokine receptor activitycomprising contacting a CCR3 receptor with an effective inhibitoryamount of a compound of claim
 1. 19. A method for treating inflammatorydisorders comprising administering to a patient in need thereof atherapeutically effective amount of a compound of claim
 1. 20. A methodfor treating disorders comprising administering to a patient in needthereof a therapeutically effective amount of a compound of claim 1,wherein the disorder is selected from asthma, allergic rhinitis, atopicdermatitis, inflammatory bowel diseases, idiopathic pulmonary fibrosis,bullous pemphigoid, helminthic parasitic infections, allergic colitis,eczema, conjunctivitis, transplantation, familial eosinophilia,eosinophilic cellulitis, eosinophilic pneumonias, eosinophilicfasciitis, eosinophilic gastroenteritis, drug induced eosinophilia, HIVinfection, cystic fibrosis, Churg-Strauss syndrome, lymphoma, Hodgkin'sdisease, and colonic carcinoma.
 21. The method of claim 20 for treatingdisorders selected from asthma, allergic rhinitis, atopic dermatitis,and inflammatory bowel diseases.
 22. A method for the modulation of thechemokine receptor CCR-3 comprising the administration of an effectiveamount of a compound of formula (I)

or stereoisomers or pharmaceutically acceptable salts thereof, wherein:Q is selected from CH₂, CHR⁵, CHR¹³, CR¹³R¹³, and CR⁵R¹³; K, and L areindependently selected from CH₂, CHR⁵, CHR⁶, CR⁶R⁶ and CR⁵R⁶; with theproviso: at least one of J, K, L, or Q contains an R⁵; is selected fromCH₂, CHR⁵, CHR¹³, and CR⁵R¹³; Z is selected from O and S; E is selectedfrom:

ring A is phenyl or naphthyl; R₁ and R₂ are independently selected fromH, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, anda (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(a); R^(a),at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂, CN,(CH₂)_(r)NR^(b)R^(b), (CH₂)_(r)OH, (CH₂)_(r)OR^(c), (CH₂)_(r)SH,(CH₂)_(r)SR^(c), (CH₂)_(r)C(O)R^(b), (CH₂)_(r)C(O)NR^(b)R^(b),(CH₂)_(r)NR^(b)C(O)R^(b), (CH₂)_(r)C(O)OR^(b), (CH₂)_(r)OC(O)R^(c),(CH₂)_(r)CH(═NR^(b))NR^(b)R^(b), (CH₂)_(r)NHC(═NR^(b))NR^(b)R^(b),(CH₂)_(r)S (O)_(p)R^(c), (CH₂)_(r)S(O)₂NR^(b)R^(b),(CH₂)_(r)NR^(b)S(O)₂R^(c), and (CH₂)_(r)phenyl; R^(b), at eachoccurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl;R^(c), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl,and phenyl; alternatively, R₂ and R₃ join to form a 5, 6, or 7-memberedring substituted with 0-3 R^(a); R³ is selected from a(CR³′R³″)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R¹⁵, and a(CR³′R³″)_(r)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R¹⁵; R³′ andR³″, at each occurrence, are selected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, and phenyl; R⁴ is absent, taken with the nitrogen to whichit is attached to form an N-oxide, or selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(q)C(O)R^(4b),(CH₂)_(q)C(O)NR_(4a)R_(4a)′, (CH₂)_(q)C(O)OR_(4b), and a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(4c); R^(4a) and R^(4a)′, ateach occurrence, are selected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, and phenyl; R^(4b), at each occurrence, is selected fromC₁₋₆ alkyl, C₂₋₈ alkenyl, (CH₂)_(r)C₃₋₆ cycloalkyl, C₂₋₈ alkynyl, andphenyl; R_(4c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR_(4a)R_(4a)′, and (OH₂)_(r)Phenyl; alternatively, R⁴ joinswith R⁷, R⁹, R¹¹ or R¹⁴ to form a 5, 6 or ₇ menibered piperidiniumspirocycle or pyrrolidinium spirocycle substituted with 0-3 R^(a); R⁵ isselected from a (CR⁵′R⁵″)_(t)—C₃₋₁₀ carbocyclic residue substituted with0-5 R¹⁶ and a (CR₅′R₅″)_(t)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R¹⁶; R⁵′and R₅″, at each occurrence, are selected from H, C₁₋₆ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl; R⁶, at each occurrence, isselected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, (CF₂)_(r)CF₃, CN, (CH₂)_(r)NR^(6a)R^(6a)′, (CH₂)_(r)OH,(CH₂)_(r)OR^(6b), (CH₂)_(r)SH, (CH₂)_(r)SR^(6b), (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(6b), (CH₂)_(r)C(O)NR^(6a)R^(6a)′,(CH₂)_(r)NR^(6d)C(O)R^(6a), (CH₂)_(r)C(O)OR^(6b), (CH₂)_(r)OC(O)R^(6b),(CH₂)_(r)S(O)_(p)R^(6b), (CH₂)_(r)S(O)₂NR^(6a)R^(6a)′,(CH₂)_(r)NR^(6d)S(O)₂R^(6b), and (CH₂)_(t)phenyl substituted with 0-3R^(6c); R_(6a) and R^(6a)′, at each occurrence, are selected from H,C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(6c);R^(6b), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl substituted with 0-3 R^(6c); R^(6c), at eachoccurrence, is selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅alkyl, and (CH₂)_(r)NR_(6d)R^(6d); R^(6d), at each occurrence, isselected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; with the proviso thatwhen any of J, K, or L is CR⁶R₆ and R₆ is halogen, cyano, nitro, orbonded to the carbon to which it is attached through a heteroatom, theother R⁶ is not halogen, cyano, or bonded to the carbon to which it isattached through a heteroatom; R⁷, is selected from H, C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(q)OH, (CH₂)_(q)SH, (CH₂)_(q)OR^(7d),(CH₂)_(q)SR^(7d), (CH₂)_(q)NR^(7a)R^(7a)′, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(7b), (CH₂)_(r)C(O)NR^(7a)R^(7a)′,(CH₂)_(q)NR^(7a)C(O)R^(7a), (CH₂)_(q)NR_(7a)C(O)H, (CH₂)_(r)C(O)OR^(7b),(CH₂)_(q)OC(O)R^(7b), (CH₂)_(q)S(O)_(p)R^(7b),(CH₂)_(q)S(O)₂NR^(7a)R^(7a)′, (CH₂)_(q)NR^(7a)S(O)₂R^(7b), C₁₋₆haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3R^(7c), and a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(7c); p1R^(7a) and R^(7a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(7e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(7e;) R^(7b), at each occurrence, isselected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆carbocyclic residue substituted with 0-2 R^(7e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(7e); R^(7c), at each occurrence, isselected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(7f)R^(7f),(CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl,(CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(7b), (CH₂)_(r)C(O)NR^(7f)R^(7f),(CH₂)_(r)NR^(7f)C(O)R^(7a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,(CH₂)_(r)OC(O)R^(7b), (CH₂)_(r)C(═NR^(7f))NR^(7f)R^(7f),(CH₂)_(r)S(O)_(p)R^(7b), (CH₂)_(r)NHC(═NR^(7f))NR^(7f)R^(7f),(CH₂)_(r)S(O)₂NR^(7f)R^(7f), (CH₂)_(r)NR⁷fS(O)₂R^(7b), and(CH₂)_(r)phenyl substituted with 0-3 R^(7e); R^(7d), at each occurrence,is selected from C₁₋₆ alkyl substituted with 0-3 R^(7e), alkenyl,alkynyl, and a c₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7c);R^(7e), at each occurrence, is selected from C₁₋₆ aikyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl; R^(7f), at each occurrence,is selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R₈ is selected fromH, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(t)phenyl substituted with 0-3R^(8a); R_(8a), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl.,(CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl; alternatively, R⁷ and R⁸join to form C₃₋₇ cycloalkyl, or ═NR^(8b); R^(8b) is selected from H,C₁₋₆ alkyl, C₃₋₆ cycloalkyl, OH, CN, and (CH₂)_(r)-pheflyl; R⁹, isselected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, F, Cl, Br, I,NO₂, CN, (CH₂)_(r)OH, (CH₂)_(r)SH, (CH₂)_(r)OR^(9d), (CH₂)_(r)SR^(9d),(CH₂)_(r)NR^(9a)R^(9a)′, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(9b),(CH₂)_(r)C(O)NR^(9a)R^(9a)′, (CH₂)_(r)NR^(9a)C(O)R^(9a),(CH₂)_(r)NR^(9a)C(O)H, (CH₂)_(r)NR^(9a)C(O)NHR^(9a),(CH₂)_(r)C(O)OR^(9b), (CH₂)_(r)OC(O)R^(9b), (CH₂)_(r)OC(O)NHR^(9a),(CH₂)_(r)S(O)_(p)R^(9b), (CR₂)_(r)S(O)₂NR^(9a)R^(9a)′,(CR₂)_(r)NR^(9a)S(O)₂R^(9b), C₁₋₆ haloalkyl, a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(9c), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(9c); R^(9a) and R^(9a)′, at eachoccurrence, are selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(9e), and a(CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(9e); R^(9b), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(9e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(9e); R^(9c), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂, CN,(CH₂)_(r)NR^(9f)R^(9f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(9b),(CH₂)_(r)C(O)NR^(9f)R^(9f), (CH₂)_(r)NR^(9f)C(O)R^(9a),(CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(9b),(CH₂)_(r)C(═NR^(9f))NR^(9f)R^(9f), (CH₂)_(r)S(O)_(p)R^(9b),(CH₂)_(r)NHC(═NR^(9f))NR^(9f)R^(9f), (CH₂)_(r)S(O)₂NR^(9f)R^(9f),(CH₂)_(r)NR^(9f)S (O)₂R^(9b), and (CH₂)_(r)phenyl substituted with 0-3R^(9e); R^(9d), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, a C₃₋₁₀ carbocyclic residue substituted with 0-3R^(9c), and a 5-6 membered heterocyclic system containing 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R^(9c); R^(9e), at each occurrence, is selectedfrom C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH,(CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(9f)R^(9f), and (CH₂)_(r)phenyl;R^(9f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl; R¹⁰, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, F, Cl, Br, I, NO₂, CN, (CH₂)_(r)OH, (CH₂)_(r)OR^(10d),(CH₂)_(r)SR^(10d), (CH₂)_(r)NR^(10a)R¹⁰′, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(10b), (CH₂)_(r)C(O)NR^(10a)R^(10a)′,(CH₂)_(r)NR^(10a)C(O)R^(10a), (CH₂)_(r)NR^(10a)C(O)H,(CH₂)_(r)C(O)OR^(10b), (CH₂)_(r)OC(O)R^(10b), (CH₂)_(r)S(O)_(p)R^(10b),(CH₂)_(r)S(O)₂NR^(10a)R^(10a)′, (CH₂)_(r)NR^(10a)S(O)₂R^(10b), C₁₋₆haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(10c), and a (CH₂)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(10c);R^(10a) and R^(10a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(10e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(10e); R^(10b), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-2 R^(10e), and a (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(10e); R^(10c), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I,F, (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(10f)R^(10f), (CH₂)_(r)OH,(CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(10b), (CH₂)_(r)C(O)NR^(10f)R^(10f),(CH₂)_(r)NR^(10f)C(O)R^(10a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,(CH₂)_(r)OC(O)R^(10b), (CH₂)_(r)C(═NR^(10f))NR^(10f)R^(10f),(CH₂)_(r)S(O)_(p)R^(10b), (CH₂)_(r)NHC(═NR^(10f))NR^(10f)R^(10f),(CH₂)_(r)S(O)₂NR^(10f)R^(10f), (CH₂)_(r)NR^(10f)S(O)₂R^(10b), and(CH₂)_(r)phenyl substituted with 0-3 R^(10e); R^(10d), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aC₃₋₁₀ carbocyclic residue substituted with 0-3 R^(10c), and a 5-6membered heterocyclic system containing 1-4 heteroatoms selected fromthe group consisting of N, O, and S substituted with 0-3 R^(10c);R^(10e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(10f)R^(10f), and (CH₂)_(r)phenyl; R^(10f), at eachoccurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆ cycloalkyl;alternatively, R⁹ and R¹⁰ join to form C₃₋₇ cycloalkyl, 5-6-meniberedcyclic ketal or ═O; with the proviso that when R¹⁰ is halogen, cyano,nitro, or bonded to the carbon to which it is attached through aheteroatom, R⁹ is not halogen, cyano, or bonded to the carbon to whichit is attached through a heteroatom; R¹¹, is selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(q)OH, (CH₂)_(q)SH,(CH₂)_(q)OR^(11d), (CH₂)_(q)SR^(11d), (CH₂)_(q)NR^(11a)R^(11a)′,(CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(11b), (CH₂)_(r)C(O)NR^(11a)R^(11a)′,(CH₂)_(q)NR^(11a)C(O)R^(11a), (CH₂)_(q)NR^(11a)C(O)NHR^(11a),(CH₂)_(r)C(O)OR^(11b), (CH₂)_(q)OC(O)R^(11b), (CH₂)_(q)S(O)_(p)R^(11b),(CH₂)_(q)S(O)₂NR^(11a)R^(11a)′, (CH₂)_(q)NR^(11a)S(O)₂R^(11b), C₁₋₆haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(11c), and a (CH₂)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(11c);R^(11a) and R^(11a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(11e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(11e); R^(11b), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-2 R^(11e), and a (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(11e); R^(11c), at each occurrence, is selected from C₁₋₄alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I,F, (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(11f)R^(11f), (CH₂)_(r)OH,(CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(11b), (CH₂)_(r)C(O)NR^(11f)R^(11f),(CH₂)_(r)NR^(11f)C(O)R^(11a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,(CH₂)_(r)OC(O)R^(11b), (CH₂)_(r)C(═NR^(11f))NR^(11f)R^(11f),(CH₂)_(r)NHC(═NR^(11f))NR^(11f)R^(11f), (CH₂)_(r)S(O)_(p)R^(11b),(CH₂)_(r)S(O)₂NR^(11f)R^(11f), (CH₂)_(r)NR^(11f)S(O)₂R^(11b), and(CH₂)_(r)phenyl substituted with 0-3 R^(11e); R^(11d), at eachoccurrence, is selected from C₁₋₆ alkyl substituted with 0-3 R^(11e),C₂₋₆ alkenyl, C₂₋₆ alkynyl, and a C₃₋₁₀ carbocyclic residue substitutedwith 0-3 R^(11c); R^(11e), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl; R^(11f), at eachoccurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R¹² isselected from H, C₁₋₆ alkyl, (CH₂)_(q)OH, (CH₂)_(r)C₃₋₆ cycloalkyl, and(CH₂)_(t)phenyl substituted with 0-3 R^(12a); R^(12a), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(9f)R^(9f), and(CH₂)_(r)phenyl; alternatively, R¹¹ and R¹² join to form C₃₋₇cycloalkyl; R¹³, at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, (CF₂)_(w)CF₃,(CH₂)_(r)NR^(13a)R^(13a)′, (CH₂)_(r)OH, (CH₂)_(r)OR^(13b), (CH₂)_(r)SH,(CH₂)_(r)SR^(13b), (CH₂)_(w)C(O)OH, (CH₂)_(w)C(O)R^(13b),(CH₂)_(w)C(O)NR^(13a)R^(13a)′, (CH₂)_(r)NR^(13d)C(O)R^(13a),(CH₂)_(w)C(O)OR^(13b), (CH₂)_(r)OC(O)R^(13b), (CH₂)_(w)S(O)_(p)R^(13b),(CH₂)_(w)S(O)₂NR^(13a)R^(13a)′, (CH₂)_(r)NR^(13d)S(O)₂R^(13b), and(CH₂)_(w)-phenyl substituted with 0-3 R^(13c); R^(13a) and R^(13a)′, ateach occurrence, are selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, andphenyl substituted with 0-3 R^(13c); R^(13b), at each occurrence, isselected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with0-3 R^(13c), R^(13c), at each occurrence, is selected from C₁₋₆ alkyl,C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl, and (CH₂)_(r)NR^(13d)R^(13d);R^(13d), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl; R¹⁴, at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(14a)R^(14a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(14d),(CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(14d),(CHR′)_(r)C(O) OH, (CHR′)_(r)C(O) (CHR′)_(r)R^(14b),(CHR′)_(r)C(O)NR^(14a)R^(14a)′, (CHR′)_(r)NR^(14f)C(O)(CHR′)_(r)R^(14b), (CHR′)_(r)C(O)O(CHR′)_(r)R^(14d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(14b), (CHR′)_(r)C(═NR^(14f))NR^(14a)R^(14a)′,(CHR′)_(r)NHC(═NR^(14f))NR^(14f)R^(14f),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(14b), (CHR′)_(r)S(O)₂NR^(14a)R^(14a)′,(CHR′)_(r)NR^(14f)S(O)₂(CHR′)_(r)R^(14b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(14e), and a (CH₂)_(r)-5-10meinbered heterocyclic system containing 1-4 heteroatoms selected fromN, O, and S, substituted with 0-2 R^(15e), or two R¹⁴ substituents onadjacent atoms on ring A form to join a 5-6 rnembered heterocyclicsystem containing 1-3 heteroatoms selected from N, O, and S substitutedwith 0-2 R^(15e); alternatively, R¹⁴ joins with R₄ to form a 5, 6 or 7membered piperidinium spirocycle or pyrrolidinium spirocycle fused toring A, the spirocycle substituted with 0-3 R^(a); R′, at eachoccurrence, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with R^(14e);R^(14a) and R^(14a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(14e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(14e); R^(14b), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)-C₂₋₆ carbocyclic residuesubstituted with 0-3 R^(14e), and (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(14e); R^(14d), at each occurrence, is selected from C₂₋₈alkenyl, C₂₋₈ alkynyl, C₁₋₆ alkyl substituted with 0-3 R^(14e), a(CH₂)_(r)-C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(14e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(14e); R^(14e), ateach occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(14f)R^(14f), and (CH₂)_(r)phenyl; R^(14f), at eachoccurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl;R¹⁵, at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(15a)R^(15a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(15d),(CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(15d),(CHR′)_(r)C(O)OH, (CHR′)_(r)C(O) (CHR′)_(r)R^(15b),(CHR′)_(r)C(O)NR^(15a)R^(15a)′, (CHR′)_(r)NR^(15f)C (O)(CHR′)_(r)R^(15b), (CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b), (CHR′)_(r)C (═NR^(15f))NR^(15a)R^(15a)′,(CHR′)_(r)NHC(═NR^(15f))NR^(15f)R^(15f),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)₂NR^(15a)R^(15a)′,(CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R^(15a) and R^(15a)′, at eachoccurrence, are selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(15e), anda (CH₂)_(r)-5-10 menibered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);R^(15b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3R^(15e), and (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);R^(15d), at each occurrence, is selected from C₂₋₈ alkenyl, C₂₋₈alkynyl, C₁₋₆ alkyl substituted with 0-3 R^(15e), a(CH₂)_(r)C₃₋ carbocyclic residue substituted with 0-3 R^(15e), and a(CN₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(15e); R^(15e), ateach occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, ON, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(15f)R^(15f), and (CH₂)_(r)pheflyl; R^(15f), at eachoccurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl;R¹⁶, at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(16a)R^(16a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(16d),(CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(16d), (CHR′)_(r)C(O) OH, (CHR′)_(r)C(O) (CHR′)_(r)R^(16b),(CHR′)_(r)C(O)NR^(16a)R^(16a)′, (CHR′)_(r)NR^(16f)C (O)(CHR′)_(r)R^(16b), (CHR′)_(r)C(O)O(CHR′)_(r)R^(16d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(16b), (CHR′)_(r)C(═NR^(16f))NR^(16a)R^(16a)′,(CHR′)_(r)NHC(═NR^(16f))NR^(16f)R^(16f),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂NR^(16a)R^(16a)′,(CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and(CHR′)_(r)phenyl substituted with 0-3 R^(16e); R^(16a) and R^(16a)′, ateach occurrence, are selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(16e), and a (CH₂)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(16e);R^(16b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3R^(16e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(16e);R^(16d), at each occurrence, is selected from C₂₋₈ alkenyl, C₂₋₈alkynyl, C₁₋₆ alkyl substituted with 0-3 R^(16e), a (CH₂)_(r)C₃₋₁₀carbocyclic residue substituted with 0-3 R^(16e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(16e); R^(16e), at each occurrence, isselected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(16f)R^(16f), and(CH₂)_(r)phenyl; R^(16f), at each occurrence, is selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl, and phenyl; g is selected from 0, 1, 2, 3,and 4; t is selected from 1 and 2; w is selected from 0 and 1; r isselected from 0, 1, 2, 3, 4, and 5; q is selected from 1, 2, 3, 4, and5; and p is selected from 0, 1, 2, and
 3. 23. The method of claim 22,wherein: E is selected from:

R⁴ is absent, taken with the nitrogen to which it is attached to form anN-oxide, or selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and(CH₂)_(r)-phenyl substituted with 0-3 R^(4c); R^(40c), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(4a)R^(4a)′, and(CH₂)_(r)phenyl; alternatively, R⁴ joins with R⁷, R⁹ or R¹⁴ to form a 5,6 or 7 membered piperidinium spirocycle substituted with 0-3 R^(a); R¹and R² are independently selected from H and C₁₋₄ alkyl; R⁶, at eachoccurrence, is selected from C₁₋₄ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, (CF₂)_(r)CF₃, CN, (CH₂)_(r)OH,(CH₂)_(r)OR^(6b), (CH₂)_(r)C(O)R^(6b), (CH₂)_(r)C(O)NR^(6a)R^(6a)′,(CH₂)_(r)NR^(6d)C(O)R^(6a), and (CH₂)_(t)phenyl substituted with 0-3R^(6c); R^(6a) and R^(6a)′, at each occurrence, are selected from H,C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(6c);R^(6b), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl substituted with 0-3 R^(5c); R^(6c), at eachoccurrence, is selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅alkyl, and (CH₂)_(r)NR^(6d)R^(6d); R^(6d), at each occurrence, isselected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R⁷, is selected fromH; C₁₋₃ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(q)OH, (CH₂)_(q)OR^(7d),(CH₂)_(q)NR^(7a)R^(7a)′, (CH₂)_(r)C(O)R^(7b),(CH₂)_(r)C(O)NR^(7a)R^(7a)′, (CH₂)_(q)NR^(7a)C(O)R^(7a), C₁₋₆ haloalkyl,(CH₂)_(r)phenyl with 0-2 R^(7c); R^(7a)and R^(7a)′, at each occurrence,are selected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a(CH₂)_(r)phenyl substituted with 0-3 R^(7e); R^(7b), at each occurrence,is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, (CH₂)_(r)phenyl substituted with 0-3 R^(7e); R^(7c), at eachoccurrence, is selected from C₁₋₄ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂, CN,(CH₂)_(r)NR^(7f)R^(7f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)C(O)R^(7b), (CH₂)_(r)C(O)NR^(7f)R^(7f),(CH₂)_(r)NR^(7f)C(O)R^(7a), (CH₂)_(r)S(O)_(p)R^(7b),(CH₂)_(r)S(O)₂NR^(7f)R^(7f), (CH₂)_(r)NR^(7f)S (O) ₂R^(7b), and(CH₂)_(r)phenyl substituted with 0-2 R^(7e); R⁷d, at each occurrence, isselected from C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(r)phenylsubstituted with 0-3 R^(7e); R^(7e), at each occurrence, is selectedfrom C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br,I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅alkyl, (CH₂)_(r)NR^(7f)R^(7f), and (CM₂)_(r)phenyl; R^(7f), at eachoccurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆ cycloalkyl; R⁸ is Hor joins with R⁷ to form C₃₋₇ cycloalkyl or ═NR^(ab); R¹¹, is selectedfrom H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(q)OH,(CH₂)_(q)OR^(11d), (CH₂)_(q)NR^(11a)R^(11a)′, (CH₂)_(r)C(O)R^(11b),(CH₂)_(r)C(O)NR^(11a)R^(11a)′, (CH₂)_(q)NR^(11a)C(O)R^(11a), C₁₋₆haloalkyl, (CH₂)_(r)phenyl with 0-2 R^(11c), (CH₂)_(r)-5-10 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R¹⁵; R^(11a) and R^(11a)′, at each occurrence,are selected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a(CH₂)_(r)phenyl substituted with 0-3 R^(11e). R^(11b), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,.(CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(r)phenyl substituted with 0-3 R^(11e);R^(11c), at each occurrence, is selected from C₁₋₄ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(11f)R^(11f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)C(O)R^(11b), (CH₂)_(r)C(O)NR^(11f)R^(11f),(CH₂)_(r)NR^(11f)C(O)R^(11a), (CH₂)_(r)S(O)_(p)R^(11b),(CH₂)_(r)S(O)₂NR^(11f)R^(11f), (CH₂)_(r)NR^(11f)S(O)₂R^(11b), and(CH₂)_(r)phenyl substituted with 0-2 R^(11e); R^(11d), at eachocdurrence, is selected from C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl,(CH₂)_(r)phenyl substituted with 0-3 R^(11e); R^(11e), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(11f)R^(11f), and(CH₂)_(r)phenyl; R^(11f), at each occurrence, is selected from H, C₁₋₅alkyl and C₃₋₆ cycloalkyl; R¹² is H or joins with R¹¹ to form C₃₋₇cycloalkyl; R¹³, at each occurrence, is selected from C₁₋₄ alkyl, C₃₋₆cycloalkyl, (CH₂)NR^(13a)R^(13a)′, (CH₂)OH, (CH₂)OR^(13b),(CH₂)_(w)C(O)R^(13b), (CH₂)_(w)C(O)NR^(13a)R^(13a)′,(CH₂)NR^(13d)C(O)R^(13a), (CH₂)_(w)S(O)₂NR^(13a)R^(13a)′,(CH₂)NR^(13d)S(O)₂R^(13b), and (CH₂)_(w)-phenyl substituted with 0-3R¹³c; R^(13a) and R^(13a)′, at each occurrence, are selected from H,C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R¹³c;R^(13b), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl substituted with 0-3 R^(13c); R^(13c), at eachoccurrence, is selected from C₁₋₆ alkyl, C₃₁₋₆ cycloalkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, and(CH₂)_(r)NR^(13d)R^(13d); R^(13d), at each occurrence, is selected fromH, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; q is selected from 1, 2, and 3; andr is selected from 0, 1, 2, and
 3. 24. The method of claim 23, wherein:ring A is selected from:

R³ is selected from a (CR³′H)_(r)-carbocyclic residue substituted with0-5 R¹⁵, wherein the carbocyclic residue is selected from phenyl, C₃₋₆cycloalkyl, naphthyl, and adamantyl; and a (CR³′H)_(r)-heterocyclicsystem substituted with 0-4 R¹⁵, wherein the heterocyclic system isselected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl,benzimidazolyl, berizothiophenyl, benzofuranyl, benzoxazolyl,benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl,indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl,pyrrazolyl, 1,2,4-triazolyl, 1,2,3- triazolyl, tetrazolyl, thiadiazolyl,thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and R⁵ is selected from(CR⁵′H)_(t)-phenyl substituted with 0-5 R¹⁶; and a(CR⁵′H)_(t)-heterocyclic system substituted with 0-3 R¹⁶, wherein theheterocyclic system is selected from pyridinyl, thiophenyl, furanyl,indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl,imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl,1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl.
 25. The method of claim 24, wherein formula(I) is:

with the proviso that at least one of K or L contains an R⁵; R¹⁶, ateach occurrence, is selected from C₁₋₈ a alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(16a)R^(16a)′, NO₂, CU, OH,(CH₂)_(r)OR^(16d), (CH₂)_(r)C(O)R^(16b), (CH₂)_(r)C(O)NR^(16a)R^(16a)′,(CH₂)_(r)NR^(16f)C(O)R^(16b), (CH₂)_(r)S(O)_(p)R^(16b),(CH₂)_(r)S(O)₂NR^(16a)R^(16a)′, (CH₂)_(r)NR^(16f)S(O)₂R^(16b), and(CH₂)_(r)phenyl substituted with 0-3 R^(16e); R^(16a) and R^(16a)′, ateach occurrence, are selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with 0-3 R^(16e); R^(16b), at eachoccurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with 0-3 R^(16e); R^(16d), at eachoccurrence, is selected from C₁₋₆ alkyl and phenyl; R^(16e), at eachoccurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and R^(16f), at eachoccurrence, is selected from H, and C₁₋₅ alkyl.
 26. The method of claim25, wherein: R⁵ is CH₂phenyl substituted with 0-3 R¹⁶; R⁹, is selectedfrom H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, F, Cl, CN, (CH₂)_(r)OH,(CH₂)_(r)OR^(9d), (CR²)_(r)NR^(9a)R^(9a)′, (CH₂)_(r)OC(O)NR^(9a),(CH²)_(r)phenyl substituted with 0-5 R^(9e), and a heterocyclic systemsubstituted with 0-2 R^(9e), wherein the heterocyclic system is selectedfrom pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl; R^(9a)andR^(9a)′, at each occurrence, are selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(9e); R^(9d), ateach occurrence, is selected from C₁₋₆ alkyl and phenyl; R^(9e), at eachoccurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; R¹⁰ is selected from H, C₁₋₈alkyl, OH, and CH2OH; alternatively, R⁹ and R¹⁰ join to form C₃₋₇cycloalkyl, 5-6-membered cyclic ketal or ═O; with the proviso that whenR¹⁰ is halogen, cyano, nitro, or bonded to the carbon to which it isattached through a heteroatom, R⁹ is not halogen, cyano, or bonded tothe carbon to which it is attached through a heteroatom; R¹¹ is selectedfrom H, C₁₋₈ alkyl, (CH₂)_(r)phenyl substituted with 0-5 R^(11e), and a(CH₂)_(r)-heterocyclic system substituted with 0-2 R^(11e), wherein theheterocyclic system is selected from pyridinyl, thiophenyl, furanyl,indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl,imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl,1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl; and R^(11e), at each occurrence, is selectedfrom C₁₋₆ alkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, OH, and(CH₂)_(r)OC₁₋₅ alkyl; R¹² is H; alternatively, R¹¹ and R¹² join to formC₃₋₇ cycloalkyl; R¹⁴, at each occurrence, is selected from C₁₋₈ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, CF₃. Cl, Br, I, F, (CH₂)_(r)NR^(14a)R^(14a)′,NO₂, CN, OH, (CH₂)_(r)OR^(14d), (CH₂)_(r)C(O)R^(14b),(CH₂)_(r)C(O)NR^(14a)R^(14a)′, (CH₂)_(r)NR^(14f)C(O)R^(14b),(CH₂)_(r)S(O)_(p)R^(14b), (CH₂)_(r)S(O)₂NR^(14a)R^(14a)′,(CH₂)_(r)NR^(14f)S(O)₂R^(14b), (CH₂)_(r)phenyl substituted with 0-3R^(14e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e), ortwo R¹⁴ substituents on adjacent atoms on ring A form to join a 5-6membered heterocyclic system containing 1-3 heteroatoms selected from N,O, and S substituted with 0-2 R^(15e); R^(14a)and R^(14a)′, at eachoccurrence, are selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with 0-3 R^(14e); R^(14b), at eachoccurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with 0-3 R^(14e); R^(14d), at eachoccurrence, is selected from C₁₋₆ alkyl and phenyl; R^(14e), at eachoccurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; R^(14f), at each occurrence,is selected from H, and C₁₋₅ alkyl; and r is celected from 0, 1, and 2.27. The method of claim 26, wherein: K is selected from CH₂ and CHR⁵; Lis selected from CH₂ and CHR⁵; with the proviso that at least one of Kor L is CHR⁵; R³ is a c₃₋₁₀ carbocyclic residue substituted with 0-3R¹⁵, wherein the carbocyclic residue is selected from cyclopropyl,cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a(CR³′H)_(r)-heterocyclic system substituted with 0-3 R¹⁵, wherein theheterocyclic system is selected from pyridinyl, thiophenyl, furanyl,indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl,imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl,piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl,thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and R¹⁵,at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(15a)R^(15a)′, NO₂, CN, OH,(CH₂)_(r)OR^(15d), (CH₂)_(r)C(O)R^(15b), (CH₂)_(r)C(O)NR^(15a)R^(15a)′,(CH₂)_(r)NR^(15f)C(O)R^(15b), (CH₂)_(r)S(O)_(p)R^(15b),(CH₂)_(r)S(O)₂NR^(15a)R^(15a)′, (CH₂)_(r)NR^(15f)S(O)₂R^(15b), and(CH₂)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R^(15a) and R^(15a)′, at eachoccurrence, are selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with 0-3 R^(15e); R^(15b), at eachoccurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with 0-3 R^(15e); R^(15d), at eachoccurrence, is selected from C₁₋₆ alkyl and phenyl; R^(15e), at eachoccurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and R^(15f), at eachoccurrence, is selected from H and C₁₋₅ alkyl.